KR20120006006A - Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1h-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compositions and uses thereof - Google Patents

Abstract

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Provided are solid phase dispersions, solid phase molecular complexes, salts and crystalline polymorphs comprising Formula (I).
<Formula I>

Description

Propane-sulfonic acid # 3- [5- (4-chloro-phenyl) -lH-pyrrolo [2,3-v] pyridine-3-carbonyl] -2,4-difluoro-phenyl-amide Composition and its use {PROPANE-1-SULFONIC ACID # 3- [5- (4-CHLORO-PHENYL) -1H-PYRROLO [2,3-B] PYRIDINE-3-CARBONYL] -2,4-DIFLUORO-PHENYL® -AMIDE COMPOSITIONS AND USES THEREOF}

Disclosed are compositions comprising compounds, for example biologically active compounds, and methods of making such compositions.

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2 in PCT Application Publication No. WO 2007/002325. , 4-difluoro-phenyl} -amide is disclosed (see, eg, page 80 and the corresponding formula (page 82)).

The present invention provides compositions comprising or related to compound I. As used herein, “Compound I” refers to propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -lH-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4 -Difluoro-phenyl} -amide (the compound also uses the nomenclature " propane-1-sulfonic acid {3- [5- (4-chlorophenyl) -1 H-pyrrolo [2,3-b] pyridine- 3-carbonyl-2,4-difluoro-phenyl] -amide} ", and salts of such compounds (including pharmaceutically acceptable salts), conjugates of such compounds, of such compounds Derivatives, forms of such compounds, and prodrugs of such compounds. Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -lH-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide The structure of is given below.

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide

As used herein, the term "solid dispersion" means any solid composition having two or more components. In certain embodiments, the solid phase dispersions disclosed herein preferably comprise the active ingredient (eg compound I) dispersed in one or more other components, for example a polymer. In certain embodiments, the solid phase dispersions disclosed herein are pharmaceutical dispersions comprising one or more pharmaceutically or biologically active ingredients (eg, compound I). In some embodiments, the solid dispersion comprises Compound I dispersed molecularly in a polymer. Preferably, the solid phase dispersion is in a single phase system. Particularly preferred solid dispersions according to the invention are microprecipitated bulk powders (MBP) comprising compound I.

As used herein, the term “dispersed molecularly” refers to the random distribution of a compound (eg, compound I) into a polymer. In certain embodiments, the compound is present in the polymer in the final subdivision state. See, eg, M. G., Vachon et al., J. Microencapsulation, 14: 281-301 (1997) and Vandelli et al ,. J. Microencapsulation, 10: 55-65 (1993). In some embodiments, a compound (eg, compound I) may be dispersed in a matrix formed by the polymer in its solid state such that the compound is fixed in an amorphous form. Whether the compound is dispersed molecularly in the polymer can be demonstrated by various methods, for example, the formation of a solid phase molecular complex with a single glass transition temperature.

As used herein, the term "solid phase molecular complex" means a solid phase dispersion comprising Compound I dispersed molecularly in a polymer matrix.

As used herein with reference to the immobilization of the active compound in the polymer matrix, the term "freeze" refers to the molecules of the compound interacting with the molecules of the polymer such that the molecules of the compound are bound in the above-mentioned matrix and crystal nucleation occurs due to the lack of mobility. It means to be prevented. In some embodiments, the polymer may prevent intermolecular hydrogen bonding or weak dispersing force between two or more drug molecules of Compound I. See, eg, Matsmoro and Zografi, Pharmaceutical Research, Vo. 16, No. 11, p 1722-1728, 1999.

Thus, in a first aspect, a solid phase dispersion comprising Compound I and a polymer is provided. Also provided are solid phase molecular complexes comprising Compound I and a polymer. The polymer may be a non-ionic polymer or an ionic polymer. In certain embodiments, the polymer is selected from the group consisting of hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, methacrylic acid copolymers, and the like, as well as mixtures of two or more thereof. In some embodiments, the ratio of the weight basis amount of Compound I in the solid dispersion or solid phase molecular complex to the weight basis amount of the ionic polymer therein is about 1: 9 to about 5: 5. In one preferred embodiment of the invention, the ratio of the weight basis amount of compound I in the solid dispersion or solid phase molecular complex to the weight basis amount of the ionic polymer therein is from about 2: 8 to about 4: 6. In various embodiments, the ratio of compound I to polymer in the solid dispersion is not 1: 1, for example about 2: 8, or about 3: 7, or about 4: 6. In one preferred embodiment, the ratio of the weight basis amount of compound I in the solid dispersion or solid phase molecular complex to the weight basis amount of the ionic polymer therein is about 3: 7. In certain preferred embodiments, Compound I is about 0.1% to about 80% by weight of the solid dispersion, or about 10% to about 70% by weight of the solid dispersion, about 20% to about 60% of the solid dispersion in the solid dispersion. Weight percent, or from about 20% to about 40% by weight of the solid dispersion, or about 30% by weight of the solid dispersion. In certain embodiments of the solid phase dispersion, the polymer may be in the solid phase in an amount of at least about 20% by weight of the solid dispersion, or from about 20% to about 95% by weight of the solid dispersion, or from about 20% to about 70% by weight of the solid dispersion. May be present in the dispersion.

In certain preferred embodiments, Compound I is at least 2 months at 25 ° C, or at least 6 months at 25 ° C, or at least 12 months at 25 ° C, or at least 15 months at 25 ° C, or at least 18 months at 25 ° C, or 25 At least 24 months at ° C, or at least 2 months at 40 ° C and 75% relative humidity, or at least 4 months at 40 ° C and 75% relative humidity, or at least 5 months at 40 ° C and 75% relative humidity, or 40 ° C and 75 Stable in solid dispersions (or solid molecular complexes) for at least 6 months at% relative humidity. In certain preferred embodiments, Compound I is fixed at least 3 weeks at 40 ° C. and 75% relative humidity, or at least 1 month at 40 ° C. and 75% relative humidity, or at least 2 months at 40 ° C. and 75% relative humidity, or At least 3 months at 40 ° C and 75% relative humidity, or at least 4 months at 40 ° C and 75% relative humidity, or at least 5 months at 40 ° C and 75% relative humidity, or at least 6 months at 40 ° C and 75% relative humidity. It is mainly in amorphous form in solid dispersion or solid phase molecular complex.

In some embodiments, compound I is present in the complex as tosylate salt or mesylate salt. The complex may further comprise a pharmaceutically acceptable carrier.

As used herein, the term “mainly amorphous form” refers to greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80% of the compounds present in the composition. Or greater than 85%, or greater than 90%, or greater than 95% of the compound is in an amorphous form.

The term "about" as used herein in the context of quantitative measurements means ± 10% of the indicated amount. For example, "about 2: 8" means 1.8-2.2: 7.2-8.8.

As used herein in the context of a pharmaceutical or biologically active compound (eg, compound I), the term “stable” refers to the ability of a compound to maintain its activity under certain specified conditions or to maintain certain physical or chemical properties. In some embodiments, at the end of the specified period, the activity is at least 50%, or at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or 90% of the compound activity at the beginning of the specified period. At least, or at least 95%, or at least 98%, the active compound is "stable". In some embodiments, the compound in amorphous form is at least 50%, or at least 60%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or It is stable if at least 98% of the compounds remain in the amorphous form at the end of the specified period. In further embodiments, the amorphous compound is stable unless it forms any detectable crystalline peak in the powder XRD profile for the specified period of time.

The term "methacrylic acid copolymer" as used herein refers to methacrylic acid copolymer, methacrylic acid-methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, ammonium methacrylate copolymer, aminoalkyl methacrylate Rate copolymers and the like. In certain embodiments, a "methacrylic acid copolymer" is selected from EUDRAGIT® L 100 and Edragit® L 12,5 ("methacrylic acid copolymer, type A", "meta Also referred to as or consistent with "methacrylate-methyl methacrylate copolymer (1: 1)", "methacrylic acid copolymer L", "DMF 1242" or "PR-MF 6918"), edragit (registered Trademark) S 100 and Edragit® S 12,5 ("methacrylic acid copolymer, type B", "methacrylic acid-methyl methacrylate copolymer (1: 2)," "methacrylic acid Also referred to or consistent with Copolymer S "," DMF 1242 "or" PR-MF 6918 "), Edragit® L 100-55 (" Methacrylic Acid Copolymer, Type C "," Meta Also referred to as or consistent with "crylic acid-ethyl acrylate copolymer (1: 1) type A", "dry methacrylic acid copolymer LD" or "DMF 2584"), Edragit® L 30 D -55 ("methacrylate ball Polymer Dispersion "," Methacrylic Acid-Ethyl Acrylate Copolymer (1: 1) Dispersion 30 Per Cent "," Methacrylic Acid Copolymer LD "," JPE DMF 2584 "," PR-MF 8216 "or equivalent thereto, Edragit® FS 30 D (also referred to as" DMF 13941 "or" DMF 2006-176 "), Edragit® RL 100 ( "Ammonio methacrylate copolymer, type A", "Ammonio methacrylate copolymer (type A)", "Aminoalkyl methacrylate copolymer RS", "DMF 1242" or "PR-MF 6918 "(also referred to as or consistent with) 6, adragit® RL PO (" Ammonomethacrylate copolymer, type A "," Ammonomethacrylate copolymer (type A) "," Amino Alkyl methacrylate copolymer also referred to as or consistent with "RS" or "DMF 1242"), Edragit® RL 12,5 ("Ammiomethacrylate" Also referred to as or consistent with polymers, type A "," ammonio methacrylate copolymer (type A) "," DMF 1242 "or" PR-MF 6918 "), Edragit® L 100- 55 (also referred to as "methacrylic acid copolymer, type C", "methacrylic acid-ethyl acrylate copolymer (1: 1) type A", "dry methacrylic acid copolymer LD", "DMF 2584" or Corresponding to this), Edragit® L 30 D-55 ("Methacrylic acid copolymer dispersion" NF "Methacrylic acid-ethyl acrylate copolymer (1: 1) dispersion 30 percent", Also referred to as or consistent with "methacrylic acid copolymer LD", "DMF 2584" or "PR-MF 8216"), Edragit® FS 30 D ("DMF 13941" or "DMF 2006-176) "Also referred to as, or consistent with," Edragit® RL 100 ("Ammiomethacrylate methacrylate copolymer, type A", "Ammiomethacrylate methacrylate copolymer (type A)", "A Minoalkyl methacrylate copolymer RS ", also referred to as or consistent with" DMF 1242 "or" PR-MF 6918 "), Edragit® RL PO (" ammonio methacrylate copolymer, type A "," ammonio methacrylate copolymer (type A) ", also referred to as or consistent with" aminoalkyl methacrylate copolymer RS "or" DMF 1242 "), Edragit® RL 12 , 5 (also referred to as or consistent with "Ammonomethacrylate copolymer, type A" "Ammmonio methacrylate copolymer (Type A)", "DMF 1242" or "PR-MF 6918"), Ed Also referred to or consistent with Lagit® RL 30 D (“Ammiomethacrylate Copolymer Dispersion, Type A”, “Ammmonio Methacrylate Copolymer (Type A)” or “DMF 1242” ), Edragit® RS 100 ("Ammiomethacrylate Copolymer, Type B", NF " Monio methacrylate copolymer (type B) "," aminoalkyl methacrylate copolymer RS ", also referred to as or consistent with" DMF 1242 "or" PR-MF 6918 "), edragit (registered trademark) ) RS PO (also referred to as "ammonio methacrylate copolymer, type B", "ammonio methacrylate copolymer (type B)", "aminoalkyl methacrylate copolymer RS" or "DMF 1242" or Matched), Edragit® RS 12,5 ("Ammonio methacrylate copolymer, type B" (NF polymer is consistent with "Ammonio methacrylate copolymer (Type B)") , Also referred to as or consistent with “DMF 1242” or “PR-MF 6918”); Edragit® RS 30 D (“Ammiomethacrylate Copolymer Dispersion, Type B” (NF polymer is consistent with “Ammiomethacrylate methacrylate copolymer (Type B)”) or “DMF 1242 "Also referred to as or consistent with", Edragit® E 100 ("amino methacrylate copolymer", NF "basic butylated methacrylate copolymer", "aminoalkyl methacrylate copolymer E ", Also referred to as or consistent with" DMF 1242 "or" PR-MF 6918 "), Edragit® E PO (" basic butylated methacrylate copolymer "," aminoalkyl methacrylate aerial " Also referred to as or consistent with "Copolymer E", "Amino methacrylate copolymer", "DMF 1242"), Edragit® E 12,5 ("Amino methacrylate copolymer", "Basic Butyl Methacrylate copolymer "," DMF 1242 "or" PR-MF 6918 " I or equivalent), Edragit® NE 30 D ("ethyl acrylate and methyl methacrylate copolymer dispersion", "polyacrylate dispersion 30 percent", ("poly (ethyl acrylic Late-methyl methacrylate) -dispersion 30% ")," ethyl acrylate methyl methacrylate copolymer dispersion ", also referred to as or consistent with" DMF 2822 "or" PR-MF 6918 "), Lagit® NE 40 D (also referred to as or consistent with "DMF 2822"), Edrazit® NM 30 D ("30% polyacrylate dispersion", "(poly (ethyl Acrylate-methyl methacrylate) -dispersion 30%) ", or" DMF 2822 "or is also equivalent to), platoid (PLASTOID®) B (also referred to as or" DMF 12102 " Match).

In a second aspect, a method for preparing a solid phase dispersion or solid phase molecular complexes disclosed herein is provided. The method may comprise the use of compound I in the form of tosylate or mesylate salts.

In a third aspect, crystalline polymorph Form 1 of Compound I is provided. In certain embodiments, Crystalline Polymorph Form 1 of Compound I has a characteristic peak of 2θ at approximately 4.7, 9.4, 11.0, 12.5, and 15.4 °, or approximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 18.6 and Powder x-ray diffraction pattern with characteristic peaks of 2θ at 22.2 °, or characteristic peaks of 2θ at approximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 16.1, 18.6, 19.0, 22.2 and 26.8 ° Indicates. In certain embodiments, Crystalline Polymorph Form 1 of Compound I exhibits a powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern of FIG. 1. Also provided are methods of preparing the solid dispersions and solid molecular complexes described herein, wherein the solid dispersions or solid molecular complexes are prepared from Compound I in the form of crystalline polymorph Form 1.

In a fourth aspect, crystalline polymorph Form 2 of Compound I is provided. In certain embodiments, Crystalline Polymorph Form 2 of Compound I has a characteristic peak of 2θ at approximately 8.8, 9.2, 13.5, 19.1, and 24.4 °, or approximately 6.7, 8.8, 9.2, 13.5, 15.0, 17.7, 19.1, 19.7, Characteristic peaks of 2θ at 21.4 and 24.4 °, or 2θ at approximately 6.7, 8.8, 9.2, 13.5, 14.1, 14.5, 15.0, 16.2, 17.0, 17.7, 19.1, 19.7, 21.4, 22.2, 24.1, 24.4, and 28.1 ° Powder x-ray diffraction pattern with a characteristic peak of. In certain embodiments, Crystalline Polymorph Form 2 of Compound I exhibits a powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern of FIG. 2. Also provided is a process for preparing the solid dispersions and solid molecular complexes described herein, wherein the solid dispersion or solid molecular complex is prepared from Compound I in the form of crystalline polymorph Form 2.

All atoms in the compounds described herein are intended to include any isotopes thereof, unless expressly stated to the contrary. Of course, for any given atom, the isotopes may be present essentially at their natural rate, or one or more specific atoms may be enriched for one or more isotopes using synthetic methods known to those skilled in the art. have. Thus, hydrogen includes, for example, ¹ H, ² H, ³ H, carbon includes, for example, ¹¹ C, ¹² C, ¹³ C, ¹⁴ C, and oxygen, for example, ¹⁶ O, ¹⁷ O, ¹⁸ O, nitrogen includes, for example, ¹³ N, ¹⁴ N, ¹⁵ N, sulfur includes, for example, ³² S, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ³⁷ S, ³⁸ S, fluorine includes, for example, ¹⁷ F, ¹⁸ F, ¹⁹ F, chlorine includes, for example, ³⁵ Cl, ³⁶ Cl, ³⁷ Cl, ³⁸ Cl, ³⁹ Cl, and the like. Is the same as

As used herein, the term “solid form” refers to a solid preparation (ie, neither gas nor liquid) of a pharmaceutical active compound suitable for administration to an animal subject for therapeutic purposes. Solid phase forms include any complex, such as salt, co-crystal or amorphous complex, as well as any polymorph of a compound. The solid phase form may be substantially crystalline, semi-crystalline or substantially amorphous. Solid form may be administered directly or used in the formulation of suitable compositions having improved pharmaceutical properties. For example, the solid form can be used in formulations comprising one or more pharmaceutically acceptable carriers or excipients.

As used herein, a material that is substantially crystalline includes a material having a crystallinity of greater than about 90%, and a "crystalline" material includes a material having a crystallinity of greater than about 98%.

The term "substantially amorphous" material as used herein includes materials having a crystallinity of about 10% or less, and "amorphous" materials include materials having crystallinity of about 2% or less.

The term "semi-crystalline" material as used herein includes materials having a crystallinity of greater than 10%, but no greater than 90%, and preferably the "semi-crystalline" material is greater than 20%, but 80 Includes substances with a crystallinity of up to%. In one aspect of the invention, a mixture of solid forms of a compound, for example a mixture of amorphous and crystalline solid forms, may be prepared, such as to provide a "semi-crystalline" solid form. Such "semi-crystalline" solid forms can be prepared by methods known in the art, for example by mixing the amorphous solid forms with the crystalline solid forms in the desired proportions. In some cases, semi-crystalline solids can be prepared by the compound mixed with an acid or a base forming an amorphous complex, and applying the amount of the compound component in an excess of the stoichiometry of the compound and the acid or base in the amorphous complex, The result is a certain amount of atypical complex with excess of the compound in crystalline form based on its stoichiometry. The amount of excess compound used in the preparation of the complex can be adjusted to provide the desired ratio of amorphous complex to crystalline compound in the resulting mixture in solid form. For example, if an amorphous complex of an acid or a base and a compound has a 1: 1 stoichiometry, preparing the complex having a molar ratio of compound to acid or base of 2: 1 yields 50% amorphous complex and 50% crystalline. It will be in the solid form of the compound. Such solid form mixtures may be advantageous as pharmaceuticals, for example by providing amorphous components with crystalline components with improved biopharmaceutical properties. Atypical components will be more readily bioavailable, while crystalline components will have delayed bioavailability. Such mixtures can provide rapid and prolonged exposure to the active compound.

As used herein, the term “complex” refers to a combination of additional molecular species and pharmaceutically active compounds that form or produce new chemical species in solid form. In some cases, the complex may be a salt, ie, an acid / base interaction that provides acid / base counter ions to the acid / base groups of the additional molecular species to form a typical salt. While such salt forms are typically substantially crystalline, they may also be partially crystalline, substantially amorphous, or atypical forms. In some cases, additional molecular species together with the pharmaceutically active compound form non-salt co-crystals. That is, the compound and molecular species do not interact by typical acid: base interactions and still form a substantial crystalline structure. Co-crystals may also be formed from salts of compounds and additional molecular species. In some cases, the complex does not form typical salt crystals, but instead forms substantially amorphous solids, i.e., solids in which the x-ray powder diffraction pattern does not show sharp peaks (e.g., shows amorphous halo). Forming is a substantially amorphous complex that may include salt-like acid: base interactions.

As used herein, the term “stoichiometry” refers to the molar ratio of two or more reactants that are formulated to form a complex, such as the molar ratio of acid or base to compound that forms an amorphous complex. For example, a 1: 1 mixture of an acid or base that is in amorphous solid form with a compound (ie, one mole of acid or base per mole of compound) has a 1: 1 stoichiometry.

The term "composition," as used herein, refers to a pharmaceutical formulation suitable for administration to an animal subject for therapeutic purposes, containing one or more pharmaceutically active compounds (including any solid form thereof). The composition may comprise one or more additional pharmaceutically acceptable components, for example suitable carriers or excipients, to provide improved formulations of the compounds.

The term “pharmaceutically acceptable” refers to a substance that does not have a property that allows a reasonably careful physician to avoid administering the substance to a patient, taking into account the disease or condition being treated and the respective route of administration. For example, such materials are usually required to be essentially sterile, for example injectables.

In the context of the present invention, the term “therapeutically effective” or “effective amount” refers to the substance or amount of substance being effective in preventing, alleviating or ameliorating one or more symptoms of a disease or medical condition and / or prolonging the survival of a subject to be treated. . In certain embodiments, “therapeutically effective amount” of Compound I refers to the dosage and / or dosage for the period of time necessary to inhibit human b-Raf containing V600E mutation. In addition, a therapeutically effective amount will be an amount in which the therapeutically beneficial effect as a whole outweighs the toxic or undesirable side effects. The therapeutically effective amount of Compound I can vary depending on the disease state, age and weight of the subject to be treated. Thus, dosage regimens are typically adjusted by the individual requirements in each particular case and are within the skill of the art. In certain embodiments, a suitable daily dose of Compound I for adult humans may be from about 100 mg to about 3200 mg, or from about 250 mg to about 2000 mg, but may be above that upper limit, if specified. The daily dose of Compound I may be administered in a single dose or in divided doses, or may be given by subcutaneous injection for parenteral administration.

In the context of the present invention, the term "synergistically effective" or "synergistic effect" is greater than the additive effect expected based on the effect of using each compound separately when used in combination of two or more therapeutically effective compounds. Indicates an improved therapeutic effect is provided.

As used herein, the term “modulating” or “modulate” refers to the effect of altering biological activity, particularly biological activity associated with a particular biomolecule, such as a protein kinase. For example, an agonist or antagonist of a particular biomolecule may increase or decrease (eg, an agonist, an activator) or an activity (eg, an antagonist, an inhibitor) of the biomolecule, eg, an enzyme, For example, it regulates the activity of enzymes. Such activity is typically expressed, for example, in terms of the inhibitory concentration (IC ₅₀ ) or excitation concentration (EC ₅₀ ) of each of the inhibitors or activators with respect to the enzyme.

Additional aspects and embodiments will be apparent from the following detailed description and claims.

1 is a powder x-ray diffraction pattern for crystalline polymorph Form 1 of Compound I. FIG.
2 is a powder x-ray diffraction pattern for crystalline polymorph Form 2 of Compound I. FIG.
3 is a comparison of powder x-ray diffraction patterns for crystalline polymorph Form 2 and mesylate salt of Compound I.
FIG. 4 is a comparison of powder x-ray diffraction patterns for crystalline polymorph Form 2 and tosylate salt of Compound I.
5 is a schematic diagram of exemplary equipment for the preparation of solid phase dispersions (MBPs) according to steps a) to d), more specifically according to embodiment 22 of the present invention.
Fig. 6 is a detailed schematic diagram of the high shear mixing apparatus (Fig. 5 (6)).
7A and 7B show solid phase dispersion of two lots containing HPMCAS and Compound I, prepared via high shear mixer precipitation (see FIG. 7A) and conventional spray precipitation (see FIG. 7B) according to the method disclosed in Example 22. A comparison of the x-ray patterns obtained from water (MBP) is provided.

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Is a compound of the following structure.

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide (Compound I)

In some embodiments, compound I is a b-Raf kinase inhibitor. Normally functioning b-Raf is involved in signal relay from the cell membrane to the nucleus and is an active kinase only when necessary to relay this signal. However, the mutant b-Raf is constantly active, causing tumor development. V600E mutation containing mutant b-Raf is associated with a variety of tumors such as colorectal cancer, melanoma and thyroid cancer. Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Specifically targets the V600E mutation containing mutant b-Raf. Thus, such inhibitors are used for the inhibition of tumors, in particular solid tumors, for example melanoma. As mentioned previously, the phrase “Compound I” as used herein refers to propane-1-sulfonic acid {3- [5- (4-chlorophenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbox Carbonyl-2,4-difluoro-phenyl] -amide, as well as any salts, conjugates, derivatives or prodrugs thereof.

Low water solubility compounds (eg, certain compounds in crystalline form) may exhibit low bioavailability with low dissolution rates. Insufficiently bioavailable compounds can sometimes present problems with therapeutic administration to a patient due to unpredictability in dose / therapeutic effects caused by the patient's abnormal absorption into the compound. For example, food intake may potentially require a medication plan that takes into account the effects of food by affecting the patient's ability to absorb such compounds that are insufficiently biologically available. In addition, due to the unpredictable dose effect, a large stability limit on the dose may be required. In addition, due to insufficient bioavailability, high doses of compounds are required to achieve the desired therapeutic effect, resulting in potentially undesired side effects.

The amorphous form of compound I has improved water solubility compared to the crystalline form, but is unstable because of its tendency to crystallization. Therefore, it is desirable to prepare the compound I so that it can exist stably in mainly amorphous form.

Thus, in some aspects and embodiments disclosed and described herein, techniques, methods, and compositions are provided for improving the solubility and / or bioavailability of Compound I. In certain embodiments, compositions and methods are provided comprising Compound I in a composition, form or formulation having improved water solubility and / or bioavailability compared to Compound I in crystalline form, or primarily Compound I in crystalline form. .

In some embodiments, a composition is provided comprising Compound I in an amorphous form of the compound. The amorphous form of compound I may have improved water solubility compared to compound I in crystalline form. In certain embodiments, for example, the compound may be immobilized in a matrix formed by the polymer to achieve a formulation of Compound I in which Compound I is stably present in an amorphous form. See, for example, US Pat. No. 6,350,786.

Solid phase of compound I and polymer Dispersion  And solid phase molecular complexes

In some aspects and embodiments, solid phase dispersions and solid phase molecular complexes comprising Compound I are provided. For example, compound I can be dispersed in its solid state in the matrix formed by the polymer and fixed in its amorphous form. In some embodiments, the polymer may prevent intermolecular hydrogen bonding or weak dispersing force between two or more drug molecules of Compound I. See, eg, Matsmoro and Zografi, Pharmaceutical Research, Vo. 16, No. 11, p 1722-1728, 1999. In certain embodiments, solid phase dispersions provide for a large surface area to enable improved dissolution and bioavailability of compound I. In certain embodiments, the solid dispersion or solid phase molecular complex comprises a therapeutically effective amount of compound I.

In some embodiments of the invention, compound I is about 1% to about 50%, or about 10% to about 40%, or about 20% to about 35%, or about 25% to about Present in the solid dispersion in an amount of 30% by weight. In related embodiments, the polymer is present in the solid dispersion in an amount of about 0% to about 50%, or about 5% to about 60%, or 10% to about 70% by weight. In certain embodiments, the polymer is present in the solid dispersion in an amount greater than about 10 weight percent, or greater than about 20 weight percent, or greater than about 30 weight percent, or greater than about 40 weight percent, or greater than about 50 weight percent. In one preferred embodiment, the solid dispersion has about 30% by weight of compound I and about 70% by weight of the polymer.

Solid phase dispersions may comprise compound I dispersed in a non-ionic polymer. This includes (A) a method of melting a polymer and dissolving the compound in the polymer and then cooling the mixture; And (B) dissolving both the polymer and the compound of interest in the organic solvent and evaporating the solvent in a rotary evaporator, for example. The resulting solid dispersion may comprise a compound dispersed in the polymer in amorphous form.

Compound I can be dispersed in the ionic polymer to form a solid dispersion. Such solid dispersions can lead to increased solubility of compound I. This can be accomplished by a variety of methods, including the methods described above used to form dispersions in non-ionic polymers. Since the ionic polymer has a pH dependent solubility in the aqueous system, the resulting solid dispersion of compound I and the polymer is stable at the low pH of the stomach and compound I in the higher pH intestine, the site of absorption. Can be discharged. In a preferred embodiment, therefore, compound I in this solid dispersion with ionic polymer can be less separated from the polymer and fixed by the polymer in its amorphous form. Any ionic polymer can be used when practicing the present invention. Examples of such ionic polymers include hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose phthalate (HPMCP) and methacrylic acid copolymers. Since one purpose of formulating Compound I into a complex with an ionic polymer is to immobilize Compound I so that it is present in predominantly amorphous form, a polymer that is capable of immobilizing Compound I to be present in predominantly amorphous form for an extended period of time is preferred. Do. Polymers, such as HPMC-AS and Edragit® L 100-55 (methacrylic acid copolymer), predominantly in amorphous form for at least 4 weeks while immobilizing Compound I and storing at 40 ° C. and 75% relative humidity It was found that it can be present as. As such, HPMC-AS and Edragit® L 100-55 are preferred polymers for use in certain embodiments of the present invention.

HPMC-AS (available from HPMCAS or AQOAT ™, eg Shin-Etsu) is a particularly preferred polymer for use in the practice of certain embodiments of the present invention. HPMC-AS is available in AS-LF, AS-MF, AS-HF, AS-LG, AS-MG and AS-HG grades. HPMC-AS is a nonionic and relatively water insoluble high molecular weight polymer having a pH-dependent water solubility that dissolves above pH 5.2. The dissolution can be adjusted at pH 5.2 to 6.5 depending on the HPMC-AS grade used. HPMC-AS may not degrade relatively well under acidic environments and normal storage temperatures. At the same time, HPMC-AS dissolves in the basic environment of the intestine because it dissolves above pH 5.2 to improve absorption of Compound I and further improve the bioavailability of Compound I. Thus, in certain embodiments of the invention, compound I is present in the solid phase dispersion with at least one polymer selected from the above mentioned HPMC-AS grades. However, it is also contemplated that mixtures of two or more different HPMC-AS grades may be used in accordance with the present invention.

In one embodiment of the invention, the ratio of the weight basis amount of Compound I in the solid phase composite to the weight basis amount of the ionic polymer therein is from about 1: 9 to about 1: 1. In one preferred embodiment of the invention, the ratio of the weight basis amount of Compound I in the solid phase composite to the weight basis amount of the ionic polymer therein is from about 2: 8 to about 4: 6. In one preferred embodiment of the invention, the ratio of the weight basis amount of Compound I in the solid phase composite to the weight basis amount of the ionic polymer therein is about 3: 7.

In one embodiment of the invention, Compound I is present in predominantly amorphous form in the complex during storage for up to 3 weeks at 40 ° C. and 75% relative humidity. In one preferred embodiment, compound I is present in predominantly amorphous form in the complex during storage for up to 1 month at fixed and 40 ° C. and 75% relative humidity. In another preferred embodiment, compound I is present in predominantly amorphous form in the complex during storage for up to 2 months at fixed and 40 ° C. and 75% relative humidity. In another preferred embodiment, compound I is present in predominantly amorphous form in the complex during storage for up to 3 months at 40 ° C. and 75% relative humidity.

In certain embodiments, the HPMC-AS is present in the solid dispersion in an amount of about 1 wt% to about 50 wt%, or about 5 wt% to about 60 wt%, or 10 wt% to about 70 wt%. In certain embodiments, the HPMC-AS is present in the solid dispersion in an amount greater than about 10 weight percent, or greater than about 20 weight percent, or greater than about 30 weight percent, or greater than about 40 weight percent, or greater than about 50 weight percent. do.

The invention also relates to a composition comprising a solid dispersion or a solid molecular complex as disclosed herein. In addition, in addition to the solid dispersion or solid phase molecular complex, the composition may comprise a therapeutically inert, inorganic or organic carrier (eg, a pharmaceutically acceptable carrier or excipient). In addition, the pharmaceutical composition may contain additional agents such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying the osmotic pressure, buffers, coatings and antioxidants. In addition, the composition may contain a therapeutically active further compound or more than one therapeutically active compound / polymer complex (eg, solid phase dispersion or solid phase molecular complex).

In certain embodiments, the composition comprises a solid phase dispersion or a solid phase molecular complex suspended in an aqueous vehicle containing hydroxypropylcellulose (HPC). In one particularly preferred embodiment, the vehicle contains about 2% by weight of HPC. In one preferred embodiment, the composition comprises colloidal silicon dioxide (silica).

In certain embodiments, colloidal silicon dioxide may be added to further improve the stability of the solid dispersion or solid phase molecular complex. In one particularly preferred embodiment, the composition comprises at least about 0.5% colloidal silicon dioxide.

In certain embodiments, provided compositions comprise Compound I (eg, in a solid dispersion or solid molecular complex) and crospovidone (or Polyplasdone XL; disintegrant for the dosage form), magnesium Stearates (lubricants that can be used in tablet and encapsulation operations) and / or croscarmellose sodium (AcDiSol; disintegrant).

In one particularly preferred embodiment, the composition comprises a solid phase dispersion or solid phase molecular suspension suspended in an aqueous vehicle having up to 2 wt% HPC and at least about 0.5 wt% colloidal silicon dioxide.

Process for preparing solid phase molecular complex of compound I and ionic polymer

Also provided are solid phase molecular complexes disclosed herein, and methods of making compositions comprising the solid phase molecular complexes. In this method, compound I can be microprecipitated with the polymers disclosed herein (eg HPMC-AS). Microprecipitation can be accomplished by any method known in the art, such as spray drying or freeze drying, solvent-controlled precipitation, pH-controlled precipitation, hot melt extrusion and supercritical fluid techniques. Each of these methods is described in more detail below.

Once the solid dispersion is precipitated out of solution using various methods, the solid dispersion can be recovered from the solution by procedures known to those skilled in the art, such as filtration, centrifugation, washing and the like. The recovered solid molecular complexes can then be dried (eg in air, in an oven or in a vacuum) and the resulting solids can be milled, ground or finely divided into fine powders by methods known in the art. . The powder form of the solid dispersion can then be dispersed in a carrier to form a pharmaceutical composition. In one preferred embodiment, at least about 0.5% w / w colloidal silicon dioxide is added to the composition.

a) spray drying  Or lyophilized  fair

Compounds I and polymers (eg HPMC-AS) can be dissolved in common solvents with low boiling points such as ethanol, methanol, acetone and the like. By spray drying or lyophilization, the solvent is evaporated by flash evaporation at a temperature near its boiling point or under high vacuum (low vapor pressure) to cause Compound I to precipitate in the matrix formed by the polymer. In certain embodiments, compound I is in the form of mesylate or tosylate salt, and therefore preferably has improved solubility.

b) solvent controlled precipitation

Compound 1 and the polymer (eg HPMC-AS) can be dissolved in conventional solvents such as dimethylacetamide, dimethylformamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like. have. Compound I / polymer solution is added to cold (0-7 ° C., preferably 2-5 ° C.) water adjusted to an appropriate pH (eg, in many embodiments, a suitable pH is 3 or less). This allows compound I to microprecipitate in the matrix formed by the polymer (eg HPMC-AS). The microprecipitates can be washed several times with an aqueous medium until the residual solvent falls below the acceptable limits for the solvent. The "acceptable limits" for each solvent are determined in accordance with the International Conference on Harmonization (ICH).

In one preferred embodiment, compound I, an organic solvent (eg, dimethylformamide, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP), etc.) and the ionic polymer Form a solution containing. The organic solvent is preferably DMA at 20 to 25 ° C. Compound I may first be dissolved in an organic solvent to form a solution. Thereafter, the polymer is added while stirring. The mixture is then heated to about 50 to about 110 ° C, preferably to about 70 ° C.

In addition, a second solution which is 0.01 N HCl is formed. The second solution will be referred to herein as the "aqueous phase". The temperature of the aqueous phase is about 0 to about 60 ° C., preferably 5 to 15 ° C.

The aqueous phase is then circulated through the mixing chamber of the high shear mixer, where the organic phase is administered to the chamber while the chamber is operating. For example, it may be administered by a gear pump, a hose pump or a syringe pump. In one preferred embodiment, administration is performed using a gear pump with an injector nozzle facing the mixing chamber. The mixing chamber preferably comprises a rotor and a stator. The rotor and stator may each have a row of teeth, for example in one or two rows. In one preferred embodiment, the rotor and stator each have one row of teeth. The tip speed of the rotor is preferably set at about 15 to about 25 m / sec.

During the mixing process, compound I and the polymer precipitate to produce a suspension of particles of the complex of compound I and the polymer in an aqueous organic medium. Thereafter, the suspension can be passed through the dispersion apparatus a number of times to adjust the particle size of the compound particles. The suspension can then be centrifuged and washed several times with the aqueous phase to remove the organic solvent and then once with pure water. The product obtained can then be delumped and dried to give the solid composite of the present invention. During the drying process, the temperature of the composite is preferably below 40 ° C. in order to avoid recrystallization of compound I.

In certain more specific embodiments, the method comprises the following steps:

(a) dissolving Compound I and HPMCAS in the same organic solvent to provide one single organic phase,

(b) the organic phase obtained in step (a) is continuously added to the aqueous phase present in the mixing chamber equipped with two additional openings and a high shear mixing device connecting the mixing chamber to the closed loop, wherein The aqueous phase is circulated and passed through the mixing chamber,

(c) while the high shear mixer is running and the aqueous phase is passed through the mixing chamber in a closed loop, precipitating a mixture of Compound I amorphous form and HPMCAS from the aqueous phase mentioned in step (b) to form an aqueous suspension of precipitate. step,

(d) The organic solution prepared in step (a) is completely added during the operation of the high shear mixing apparatus and until the defined particle size and / or particle size distribution is obtained, and then the aqueous suspension is added to the mixing chamber. Continuously cycling to,

(e) isolating the solid phase from the suspension,

(f) washing the isolated solid phase with water, and

(g) disintegrating and drying the solid phase.

In certain more specific embodiments, the method of the invention

The organic phase in step (a) is a 35% solution of compound I and HPMCAS in DMA with a ratio of compound I to HPMCAS of 30% to 70% (w / w),

The continuous addition in step (b) is about 1 to about 10 mm away from the rotor of the high shear mixer operating at a tip speed of about 15 to about 25 m / sec and 40 to about the longitudinal axis of the high shear mixer. Through injector nozzles oriented at an angle of 50 °

The above steps are included.

In a more specific embodiment, the method of the present invention

The continuous addition in step (b) is about 2 to about 4 mm from the rotor of the high shear mixer operating at a tip speed of about 25 m / sec and at an angle of about 45 ° to the longitudinal axis of the high shear mixer Through an injector nozzle that is oriented

The above steps are included.

In certain other specific embodiments, the methods of the invention

The drying in step (g) is carried out by fluid bed drying

The above steps are included.

In a further embodiment there is provided a solid dispersion obtained by the above-mentioned method.

The dry precipitate obtained by the above process can be further processed into any type of solid pharmaceutical formulation or dosage form known to those skilled in the art. Oral dosage forms such as tablets, capsules, pills, powders, suspensions and the like are particularly preferred.

As a result, the pharmaceutical formulation thus obtained forms an additional embodiment provided herein.

The term "organic solvent" mentioned in step (a) above means any organic solvent in which both compound I and HPMCAS are miscible. Preferred organic solvents are N-methylpyrrolidone (NMP), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA) and the like, with DMA being most preferred. The amount of compound I and HPMCAS combined in the organic phase can range from about 15 to 40% by weight, preferably from about 25 to 40% by weight, most preferably about 35% by weight. The weight ratio of compound I / HPMCAS in the organic solvent is about 30/70% by weight, respectively. Preferably, the temperature of the organic solvent is adjusted to 50 to 110 ° C., preferably 60 to 90 ° C., most preferably about 70 ° C. before adding the organic solvent to the mixing chamber as mentioned in step (b). . In addition, mixtures of Compound I and HPMCAS in organic solvents are referred to herein as "organic phases" or "DMA phases."

The term "aqueous phase" mentioned in step (b) preferably consists of acidic water (pH <7, preferably less than 3), most preferably 0.01 N hydrochloric acid (HCl). The aqueous phase is maintained at a temperature of about 0 to about 60 ° C, preferably about 0 to 20 ° C, more preferably about 5 to about 15 ° C, most preferably about 5 ° C. The aqueous phase is circulated out of the base valve of the reservoir (FIG. 5 (1)) due to the stream produced by the high shear mixer or with an auxiliary pump, preferably a rotary lobe pump, and then passed through the high shear mixer to the reservoir. Return to Preferably, the exit of the loop is located below the fluid level maintained in the reservoir to prevent foaming.

The addition of the organic phase to the mixing chamber as mentioned in step (b) above is via an injector nozzle directed directly to the aqueous phase. Any conventional nozzle known to those skilled in the art can be used. Preferred injector nozzles have a central or noncentral shape and are about 1 to 10 mm in diameter. Particular preference is given to non-centered (not centered) forms and diameters of 5 mm. The injector nozzle may be directed at the rotor of the high shear mixing device at an angle of 0 to 90 °, preferably 40 to 50 °, most preferably 45 ° (α, FIG. 6). In the process according to the invention, the distance between the point of the injector nozzle and the tip of the rotor of the high shear mixing device is about 1 to 10 mm, preferably about 2 to 4 mm and most preferably about 2.6 mm. Preferably, the addition of the organic phase is about 60/1 to about 300/1 (ratio of aqueous phase / organic phase during precipitation), preferably about 70/1 to about 120/1, most preferably about 100 At a dosing rate of / 1. The final ratio of the aqueous phase / organic phase after precipitation is in the range of about 5/1 to 12/1, preferably 7/1 to 10/1, most preferably 8.5 / 1.

While adding (injecting) the organic phase to the aqueous phase of the mixing chamber, the high shear mixing device is operated. Any conventional high shear mixing device (rotor / stator device) known to those skilled in the art can be applied. Preferred rotor structures according to the invention use a rotor / stator device having radial single tooth rows or double tooth rows or a combination thereof. The tip speed of the rotor is about 15 to about 25 m / sec, preferably 25 m / sec.

After complete addition of the organic phase to the aqueous phase, the suspension obtained, and thus the precipitate consisting of amorphous Compound I and HPMCAS in the aqueous phase, is further circulated in a closed loop containing a high shear mixing device. Outside the high shear mixing device, the circulation must be carried out with the aid of an auxiliary pump, preferably a rotary lobe pump. The suspension is passed through the high shear mixing apparatus several times until the desired particle size and / or particle size distribution is obtained. Usually, the suspension is passed through the high shear mixing apparatus about 1 to 60 times, most preferably 6 times. Particle size and / or particle size distribution can be measured by standard techniques well known to those skilled in the art, for example by dynamic light scattering. Preferred particle sizes according to the invention are in the range of D50 = 80 to 230 μm, preferably D50 = 80 to 160 μm.

Isolation of the solid dispersion (MBP) according to step (e) can be carried out using conventional filtration techniques or centrifugation. Prior to isolation, the suspension is preferably adjusted to about 5-10 ° C. The isolated solid dispersion is then washed with acidic water, preferably 0.01 N HCl, followed by further washing with pure water to substantially remove the organic solvent (step (f)). Isolated (wet) solid dispersion (MBP) usually exhibits a water content of 60 to 70% (w / w) and is preferably dried before any further processing. Drying can be carried out using any standard technique known to those skilled in the art, for example using a cabinet dryer at a temperature of 30 to 50 ° C., preferably at about 40 ° C. and at reduced pressure, preferably below 20 mbar. Can be. Several drying procedures can be used in combination or in succession, whereby it is particularly preferred to use fluid bed drying as the final drying step according to the invention.

The specific process for preparing (HPMCAS-Compound I) MBP according to steps a) to g) above is described in Example 22, which forms a further preferred embodiment of the invention. The stability of the solid dispersion (MBP) obtained by the method of Example 22 was compared with that of MBP obtained via conventional spray precipitation. "Typical spray precipitation" means spraying the organic phase onto the aqueous phase through a nozzle located outside its aqueous phase, as is the case for many conventional spray precipitation techniques, over its surface. All additional process parameters are the same for both methods. The stability of compound I, and thus the inhibition of recrystallization, is determined by x-ray diffraction measurements using conventional wide-angle x-ray scattering equipment such as is well known to those skilled in the art. Sample preparation was the same for both MBPs. Samples were treated for several hours (0 h, 14 h, 41 h, 4 d, 6 d, 13 d) each day in a climatic chamber (50 ° C. and 90% humidity (RH)) prior to x-ray measurements. The results are shown in FIG. 7A for the MBP obtained according to Example 22 and in FIG. 7B for the MBP obtained by conventional methods. The initial x-ray curves of both MBPs show a wide halo in the wide-angle region without a pronounced signal, demonstrating that both materials are atypical. Within a few days, a distinct signal occurs in x-rays obtained from MBPs produced by conventional methods (see FIG. 7B), but not in x-rays obtained from MBPs prepared using the methods disclosed herein (see FIG. 7A). ).

In short, the results shown in FIGS. 7A and 7B show high shear precipitation of spray precipitated MBP as evidenced by the initial generation of distinct signals (see FIG. 7B) within diffractograms that can be assigned to the crystalline forms of Compound I (see FIG. 7B). It proves less stable against recrystallization than MBP. The bottom line in each figure represents the initial sample, followed by lines from below, after 14, 41, 96, 6, and 13 days storage, respectively, in a climate controlled chamber (at 50 ° C., 90% RH). Indicates.

The novel process provided herein can be carried out preferably using the equipment shown in FIG. 5 attached.

The equipment substantially shown in FIG. 5 can be used for the following recipe. 5 shows two reservoirs with temperature control means, one reservoir 1 for providing the aqueous phase at a controlled temperature and the other reservoir 2 for providing the organic phase at a controlled temperature. Courage). Both vessels are additionally equipped with an automatic stirrer 3. The aqueous phase is circulated in the closed loop 4 using the pump 5 while passing through the high shear mixing device 6. The organic phase is added via the injector nozzle with the aid of a dosing pump 7 to the aqueous phase in the high shear mixing apparatus, which is shown in more detail in FIG. 6.

As shown in FIG. 6, the nozzle 8 is located in the aqueous phase inside the high shear mixing apparatus. The nozzles can be oriented with respect to the rotor 9 of the high shear mixing device within various angles a and within a defined distance d of the rotor tip.

Solid phase dispersions, in particular the MBPs obtainable according to the provided methods, can be used in a wide variety of forms, in particular oral dosage forms, for the administration of drugs such as compounds I, including drugs that are insufficiently water soluble. Exemplary dosage forms include powders or granules, tablets, capsules or pills that can be taken orally to dissolve to form a paste, slurry, suspension or solution by the addition of dry or water. Various additives may be mixed, ground or granulated with the solid dispersions described herein to form materials suitable for such dosage forms. Potentially beneficial additives may generally be in the following classes: other matrix materials or diluents, surface active agents, drug complexing or solubilizing agents, fillers, disintegrating agents, binders, lubricants and pH adjusting agents (eg, acids, bases or Buffer). Examples of other matrix materials, fillers or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate and starch. Examples of surface active agents include sodium lauryl sulfate and polysorbate 80. Examples of drug complexing or solubilizing agents include polyethylene glycol, caffeine, xanthene, gentis acid and cyclodextrin. Examples of disintegrants include sodium starch glycolate, sodium alginate, carboxymethyl cellulose sodium, methyl cellulose and croscarmellose sodium. Examples of binders include methyl cellulose, microcrystalline cellulose, starch and gums such as guar gum and tragacanth. Examples of lubricants include magnesium stearate and calcium stearate. Examples of pH adjusting agents include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, etc., sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and the like. Buffers comprising a base and generally a mixture of an acid and a salt of said acid are included. At least one function of incorporating such pH adjusters is to control the rate of dissolution of the drug, matrix polymer, or both to control local drug concentration during dissolution.

The additive may be incorporated into the solid amorphous dispersion during or after the formation of the solid amorphous dispersion. In addition to the above additives or excipients, it is potentially useful to use any conventional materials and procedures for the formulation and preparation of oral dosage forms using the compositions disclosed herein known to those skilled in the art.

As a result, further embodiments provide pharmaceutical preparations containing a solid dispersion obtained by the process disclosed herein, in particular obtained according to the above-mentioned steps a) to g), more particularly according to the method described in Example 22. Include.

In another embodiment, a solid dispersion obtained according to the process of the invention for use as a medicament, in particular a solid dispersion comprising HPMCAS and Compound I, more particularly according to steps a) to g) above or in Example 22 A solid dispersion obtained according to this is provided.

In another embodiment, a solid dispersion of the solid dispersion obtainable by steps a) to g) of the invention or by the method of example 22, for the treatment of cancer, in particular solid tumors, more particularly malignant (metastatic) melanoma Uses in the manufacture of a medicament are provided.

In another embodiment, use as a medicament for the treatment of cancer, in particular solid tumors, more particularly malignant (metastatic) melanoma, obtainable by steps a) to g) of the invention or by the method of example 22 Solid phase dispersions are provided for this purpose.

c) pH -Controlled precipitation

The process involves microprecipitation of compound I in ionic polymers (eg HPMC-AS). In this method, the compound I and the polymer are dissolved at high pH and precipitated by lowering the pH of the solution or vice versa.

In a preferred embodiment, the polymer is HPMC-AS, which is insoluble at low pH. Compounds I and HPMC-AS are dissolved in organic solvents such as dimethylformamide, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like. The pH of the solution is then lowered, for example by adding acid. Addition of the acid includes mixing the compound I and the polymer solution and the acid, for example, by adding the acid to the compound I and the polymer solution, adding the compound I and the polymer solution to the acid, or mixing them simultaneously. . At the lowered pH, both compound I and HPMC-AS precipitate simultaneously, producing a solid phase molecular complex containing compound I sandwiched in the matrix formed by HPMC-AS. The resulting solid phase molecular complex can then be washed with water to remove the organic solvent.

d) hot melt extrusion process

Microprecipitation of compound I in a polymer (eg HPMC-AS) may be achieved by hot melt extrusion processes in certain embodiments. Compound I and the polymer are mixed and subsequently fed into a temperature controlled extruder to allow compound I to be dispersed molecularly in the molten polymer. The resulting extrudate is cooled to room temperature and milled into fine powder.

e) Supercritical  Fluid process

In this process, compound I and polymer (eg HPMC-AS) are dissolved in a supercritical fluid such as liquid nitrogen or liquid carbon dioxide. The supercritical fluid is then removed by evaporation so that the microprecipitated compound I is in the matrix formed by the polymer. In another method, Compound I and the polymer (eg HPMC-AS) are dissolved in a suitable solvent. The solution can then be sprayed in a supercritical fluid that acts as an antisolvent to form a microprecipitated powder.

The resulting solid phase molecular complexes prepared in any manner can be further processed to provide suitable bioavailability. Solid-state molecular composites can be processed by roller compaction, for example blending and roller compacting composites and other powders to form ribbons or sheets, milling the ribbons or sheets, mixing with other excipients, and Encapsulate with strength 2-pc hard gelatin capsule shell.

Determination of the amorphous form of compound I

Various means, including powder x-ray diffraction, can determine whether Compound I was successfully fixed in an amorphous form. In addition, the glass transition temperature of the composite can be measured using a controlled DSC, which can also provide information whether the dispersion is multiphase or single phase. The single phase is a sign of this fixation.

Crystalline Polymorph

(A) crystalline Polymorph  Form 1

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Crystalline polymorph of (Compound I) is provided. In one embodiment, Crystalline Polymorph Form 1 is provided that exhibits a powder x-ray diffraction pattern having characteristic peaks of 2θ at approximately 4.7, 9.4, 11.0, 12.5, and 15.4 ° positions. In one embodiment, Polymorph Form 1 exhibits a powder x-ray diffraction pattern having characteristic peaks of 2θ at approximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 18.6, and 22.2 ° positions. In one embodiment, Polymorph Form 1 has a powder x-ray diffraction pattern having characteristic peaks of 2θ at approximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 16.1, 18.6, 19.0, 22.2, and 26.8 ° positions. Indicates. In one embodiment, Crystalline Polymorph Form 1 exhibits a powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern of FIG. 1. In one embodiment, purified crystalline polymorph Form 1 is provided. In one embodiment, the purified crystalline polymorph Form 1 is propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1 H-pyrrolo [2,3-b] pyridine-3-carbonyl] Used in the preparation of the mesylate or tosylate salt form of -2,4-difluoro-phenyl} -amide. In one embodiment, a pharmaceutical composition is provided comprising crystalline polymorph Form 1 and one or more excipients or carriers.

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide A process for the preparation of crystalline polymorph Form 1 of is provided. The process comprises propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1 H-pyrrolo [2,3-b] from a mixture of lower ketones and lower alcohols such as acetone: anhydrous ethanol. Recrystallization of any form of pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide. Propane-1-sulfonic acid [3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Can be recrystallized from acetone: anhydrous ethanol in a 1: 1 to 5: 1, preferably 2: 1 ratio by volume.

(B) crystalline Polymorph  Form 2

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo showing a powder x-ray diffraction pattern with characteristic peaks of 2θ at approximately 8.8, 9.2, 13.5, 19.1 and 24.4 ° positions Crystalline Polymorph Form 2 of [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide is provided. In one embodiment, Polymorph Form 2 exhibits a powder x-ray diffraction pattern having characteristic peaks of 2θ at approximately 6.7, 8.8, 9.2, 13.5, 15.0, 17.7, 19.1, 19.7, 21.4, and 24.4 ° positions. In one embodiment, Polymorph Form 2 is characteristic of 2θ at approximately 6.7, 8.8, 9.2, 13.5, 14.1, 14.5, 15.0, 16.2, 17.0, 17.7, 19.1, 19.7, 21.4, 22.2, 24.1, 24.4, and 28.1 ° positions. A powder x-ray diffraction pattern with peaks is shown. In one embodiment, crystalline polymorph Form 2 exhibits a powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern of FIG. 2. In one embodiment, purified crystalline polymorph Form 2 is provided. In one embodiment, the purified crystalline polymorph Form 2 is propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1 H-pyrrolo [2,3-b] pyridine-3-carbonyl] Used in the preparation of the mesylate or tosylate salt form of -2,4-difluoro-phenyl} -amide. In one embodiment, a pharmaceutical composition is provided comprising crystalline polymorph Form 2 and one or more excipients or carriers.

Direct crystallization from dimethylacetamide / methanol and propane-1-sulfonic acid {3- from suitable ethers (including cyclic ethers), ester or ketone solvents, for example methyl-t-butyl ether, tetrahydrofuran, ethyl acetate or acetone Recrystallization of any form of [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl } Provided are methods of preparing crystalline polymorph Form 2 of amide. In one embodiment, propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1 H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro Form 2 of -phenyl} -amide is prepared by heating / melting and restocking any form of the compound.

Of compound I Mesylate  salt

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Mesylate salt form of is provided. In one embodiment, propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1 H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro Mesylate salt form of -phenyl]}-amide is provided. In one embodiment, the mesylate salt form is substantially crystalline. In one embodiment, the mesylate salt form is partially amorphous. In one embodiment, the mesylate salt form is substantially amorphous. In one embodiment, the mesylate salt is used in the microprecipitated bulk process to formulate salts in amorphous form. In one embodiment, the mesylate salt is produced in situ in a microprecipitated bulk process for formulating the salt in an amorphous form. In one embodiment, a composition is provided comprising a mesylate salt.

Of compound I Tosylate  salt

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Tosylate salt of is provided. In one embodiment, the tosylate salt form is substantially crystalline. In one embodiment, the tosylate salt form is partially amorphous. In one embodiment, the tosylate salt form is substantially amorphous. In one embodiment, the tosylate salt is used in the microprecipitated bulk process to formulate salts in amorphous form. In one embodiment, the tosylate salt is produced in situ in a microprecipitated bulk process for formulating the salt in an amorphous form. In one embodiment, a composition comprising a tosylate salt is provided.

Kinase  Targets and Signs

Protein kinases play an important role in transmitting biochemical signals in various biological pathways. More than 500 kinases are described, and certain kinases are associated with a wide range of diseases or conditions (ie, signs) including, without limitation, for example, cancer, cardiovascular disease, inflammatory disease, neurological disease and other diseases. have. As such, kinases provide an important benchmark for therapeutic intervention of small molecules. The description of specific target protein kinases contemplated by the present invention follows.

a- Raf : Target kinase a-Raf (ie, v-raf rat sarcoma 3611 viral tumor gene homolog 1) is a 67.6 kDa serine / threonine kinase encoded by chromosome Xp11.4-p11.2 (symbol: ARAF) to be. Mature proteins include RBD (ie, Ras binding domains) and include phorbol-ester / DAG-type zinc finger domains and are involved in the conversion of mitogen signals from the cell membrane to the nucleus. a-Raf inhibitors include neurological diseases such as multiple infarction, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; Melanoma, glioma, sarcoma, carcinoma (eg, colorectal, lung, breast, pancreas, thyroid, kidney, ovary), lymphoma (eg, histiocytoma), neurofibromatosis, myelodysplastic syndrome, leukemia Tumorous diseases, including but not limited to tumor angiogenesis; Pain from neuropathic or inflammatory sources, including but not limited to acute pain, chronic pain, cancer related pain, and migraine headaches; And vascular restenosis, sarcopenia, muscle dystrophy (Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, facial scapula, muscle tone, eye Includes, but is not limited to, palpitations, distal and congenital muscle dystrophy, motor neuron diseases (amyotrophic lateral sclerosis, infantile spinal muscular atrophy, intermediate spinal muscular atrophy, pediatric spinal muscular atrophy, spinal cord atrophy, and adult spinal muscular atrophy) But not limited to), inflammatory myopathy (including but not limited to skin myositis, polymyositis and inclusion body myositis), neuromuscular junction disease (myasthenia gravis, Lambert-Eaton syndrome and congenital work history) Syndromes, including, but not limited to, myopathy due to endocrine abnormalities (including but not limited to hyperthyroidism and hypothyroidism) But not limited to, peripheral neuropathy (Charcot-Marie-Tooth disease, Dejerine-Sottas disease, and Friedreich ataxia) ), Other myopathy (including but not limited to congenital myotonia, congenital dystonia, central core disease, nemalin myopathy, myotubular myopathy and periodic paralysis), and muscle metabolic diseases (phosphorylase deficiency, Acid maltase deficiency, phosphofructokinase deficiency, debranching enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmityl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydro Muscle regeneration or degeneration, including but not limited to, genease deficiency and myoadenylate deaminase deficiency) In the treatment of diseases associated with it can be useful.

b- Raf : Target kinase b-Raf (ie, v-raf rat sarcoma viral tumor gene homolog B1) is an 84.4 kDa serine / threonine kinase encoded by chromosome 7q34 (symbol BRAF). Mature proteins include RBD (ie Ras binding domain), C1 (ie protein kinase C conserved region 1) and STK (ie seri / throscin kinase) domains.

Target kinase b-Raf is involved in the conversion of mitogen signals from the cell membrane to the nucleus and may play an important role in the postsynaptic response of hippocampal neurons. As such, the RAF family of genes encode kinases regulated by Ras and mediate cellular responses to growth signals. In fact, b-Raf kinase is a major component of the RAS-> Raf-> MEK-> ERK / MAP kinase signaling pathway, which plays an important role in the regulation of cell growth, division and proliferation, If, it causes tumor formation. Of the many isoforms of Raf kinases, the b-type or b-Raf is the most potent activator of downstream MAP kinase signaling.

The BRAF gene is frequently mutated in various human tumors, especially in malignant melanoma and colon malignancies. The most commonly reported mutation was the missense conversion of thymine (T) to adenosine (A) at nucleotide 1796 observed in 80% of malignant melanoma tumors (T1796A: amino acid changes in the b-Raf protein were Val <600 > Is Glu <600>). Functional analysis indicates that the transformation is the only mutation detected that results in the constitutive activation of b-Raf kinase activity by converting b-Raf to the dominant modified protein regardless of RAS activation. Based on precedence, human tumors develop resistance to kinase inhibitors by mutating certain amino acids to “gatekeepers” in the catalytic domain (Balak, et. Al., Clin Cancer Res. 2006, 12: 6494-501). Thus, mutation of Thr-529 to Ile in BRAF is expected to be a mechanism of resistance to BRAF inhibitors, which can be imagined as the transition from ACC to ATC at codon 529.

Nihori et al. Reported that of 43 individuals with cardio-facio-cutaneous (CFC) syndrome, 2 heterozygous KRAS mutations were identified in 3 and 8 BRAF mutations in 16, This suggests that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for three related disorders (Niihori et al., Nat Genet. 2006, 38 (3): 294-6). ).

c- Raf -1: Target kinase c-Raf-1 (i.e., v-raf rat sarcoma virus tumor gene homolog 1) is a chromosome 3p25: is a 73.0 kDa STK encoded by the (sign RAF1). c-Raf-1 can target mitochondria by BCL2 (ie, tumor gene b-cell leukemia 2), a regulator of apoptotic cell death. Active c-Raf-1 improves BCL2-mediated resistance to apoptosis, and c-Raf-1 phosphorylates BAD (ie, BCL2-binding protein). c-Raf-1 is implicated in carcinomas including colorectal, ovarian, lung and renal cell carcinoma. c-Raf-1 is also implicated as an important mediator of tumor angiogenesis (Hood, JD et al., 2002, Science 296, 2404). c-Raf-1 inhibitors may also be useful for the treatment of acute myeloid leukemia and myelodysplastic syndromes (Crump, Curr Pharm Des 2002, 8 (25): 2243-8). Raf-1 activators may be useful as treatments for neuroendocrine tumors, such as interstitial thyroid cancers, carcinoids, small cell lung cancers, and chromaffin cell tumors (Kunnimalaiyaan et al., Anticancer Drugs 2006, 17 (2): 139-42].

a-Raf, b-Raf and / or c-Raf inhibitors include but are not limited to neurological diseases including but not limited to multiple infarcts, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, seizures and epilepsy; Melanoma, glioma, sarcoma, carcinoma (eg, gastrointestinal, liver, bile duct (cholangiocarcinoma), colorectal, lung, breast, pancreas, thyroid, kidney, ovary, prostate), lymphoma (eg, histiocytes Lymphomas), neurofibromatosis, acute myeloid leukemia, myelodysplastic syndromes, leukemias, tumor angiogenesis, neuroendocrine tumors such as stromal thyroid cancer, carcinoids, small cell lung cancer, Kaposi's sarcoma, and chromophiloma Neoplastic diseases, including but not limited to; Pain from neuropathic or inflammatory sources, including but not limited to acute pain, chronic pain, cancer related pain, and migraine headaches; Cardiovascular diseases including but not limited to heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (eg, thrombotic microangiopathy syndrome), atherosclerosis and reperfusion injury; Inflammation and / or proliferation, including but not limited to psoriasis, eczema, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrosis disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); Immunodeficiency diseases, including but not limited to organ transplant rejection, graft-versus-host disease, and HIV-associated Kaposi's sarcoma; Diabetic nephropathy, polycystic kidney disease, kidney hardening, glomerulonephritis, prostate hyperplasia, polycystic liver disease, nodular sclerosis, Von Hippel Lindau disease, interstitial cystic kidney disease, kidney kidney disease, and cystic fibrosis But not limited to renal cystic or prostate disease; Metabolic disorders including but not limited to obesity; Helicobacter Helicobacter pylori), H. Party Tees (Hepatitis) and influenza (Influenza) including viruses, heat, HIV infection and sepsis, but does not have this limitation; Lung diseases, including but not limited to chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); Nuonan syndrome, Costello syndrome, facial and skeletal syndrome, LEOPARD syndrome, heart-face-skin syndrome (CFC) that cause cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases , Genetic developmental diseases, including but not limited to neuronal ridge syndrome abnormalities; sarcopenia, muscular dystrophy (dubrain, Becker, Emery-Dreyfuss, zonal, facial scapula, muscle tension, osopharyngeal muscle, Including but not limited to distal and congenital muscular dystrophy, motor neuron disease (myotrophic lateral sclerosis, infantile spinal muscular atrophy, intermediate spinal muscular atrophy, pediatric spinal muscular atrophy, spinal cord atrophy, and adult spinal muscular atrophy) Inflammatory myopathy (including but not limited to skin myositis, polymyositis and inclusion body myositis), neuromuscular junction disease (severe) Myasthenia gravis, Lambert-Etonton syndrome and congenital work syndrome, myopathy due to endocrine abnormalities (including but not limited to hyperthyroidism and hypothyroidism), peripheral nerves Diseases (including but not limited to Sharco-Marie-Tut disease, Deserin-Sotas disease, and Friedreich's ataxia), other myopathy (congenital myotonia, congenital dystonia, central core disease, nemenin myopathy) , Myocardial myopathy and periodic paralysis, and muscle metabolic diseases (phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debranching enzyme deficiency, mitochondrial myopathy, carnitine Deficiency, Carnitine Palmityl Transferase Deficiency, Phosphoglycerate Kinase Deficiency, Phosphoglycerate Mutase Deficiency, Lac A-Raf-mediated selected from the group consisting of diseases related to muscle regeneration or degeneration, including but not limited to tate dehydrogenase deficiency and myoadenylate deaminase deficiency) , b-Raf-mediated or c-Raf-1-mediated diseases or conditions.

Alternative compound form or derivative

Propane-1-sulfonic acid {3- [5- (4-chlorophenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl-2,4-difluoro-phenyl] contemplated herein -Amide} has been described for specific compounds. In addition, compound I can exist in many different forms or derivatives, all within the scope of the present invention. Alternative forms or derivatives include, for example, (a) prodrugs and active metabolites (b) tautomers, (c) pharmaceutically acceptable salts, and (d) various crystalline form polymorphs or amorphous solid forms ( Solid forms, including hydrates and solvates thereof, and other forms.

Prodrug  And Metabolite

Prodrugs are compounds or pharmaceutically acceptable salts thereof which yield the desired active compounds when metabolized under physiological conditions or converted by solvation digestion. Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates or hydrates of the active compounds. Typically, prodrugs are inert or less active than active compounds, but can provide one or more advantageous handling, administration, and / or metabolic properties. Prodrugs include variants in which the nitrogen is acylated at the —NH group of the compound, for example the 1-position of the pyrrolo [2,3-b] pyridine ring or the sulfonamide group of compound I or a pharmaceutically acceptable salt thereof. Wherein the degradation of the acyl group provides the free -NH group of the active drug. Some prodrugs may be enzymatically activated to yield the active compound, or the compound may be further chemically reacted to obtain the active compound. Prodrugs may have one or more intermediate forms that may reach the active form in the prodrug form in a single step or may be active on their own or inactive.

[ The Practice of Medicinal Chemistry , Ch. As described in 31-32 (Ed. Wermuth, Academic Press, San Diego, CA, 2001), prodrugs may be conceptually divided into two non-exclusive categories: bioprecursor prodrugs and carrier prodrugs. . In general, bioprecursor prodrugs are compounds that are inert or less active than the corresponding active drug compound, which contain one or more protecting groups and are converted into active forms by metabolism or solvation degradation. Both the active drug form and any released metabolite should be tolerably low in toxicity. Typically, the formation of the active drug compound comprises a metabolic process or reaction of one of the following types.

Oxidation reactions : oxidation reactions include oxidation of alcohol, carbonyl and acid functionalities, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, nitrogen-containing functional groups Are exemplified without limitation by reactions such as oxidation, oxidation of silicon, phosphorus, arsenic and sulfur, oxidized N-dealkylation, oxidized O- and S-dealkylation, oxidative deaminoation, and also other oxidation reactions.

Reduction Reaction : The reduction reaction is exemplified without limitation by the reduction of carbonyl functional groups, the reduction of alcohol functional groups and carbon-carbon double bonds, the reduction of nitrogen-containing functional groups and other reduction reactions.

Reactions in which the oxidation state does not change: reactions in which the oxidation state does not change include hydrolysis of esters and ethers, hydrolytic decomposition of carbon-nitrogen single bonds, hydrolytic decomposition of nonaromatic heterocycles, hydration and dehydration at multiple bonds, New atomic bonds resulting from dehydration reactions, hydrolysable dehalogenation, removal of hydrogen halide molecules and other such reactions are exemplified without limitation.

Carrier prodrugs are drug compounds containing carrier moieties that improve, for example, uptake and / or local delivery to the site (s) of action. Preferably, for such carrier prodrugs, the bond between the drug moiety and the carrier moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and the prodrug and any release carrier moiety are acceptable nontoxic. to be. For prodrugs where the carrier moiety is intended to improve uptake, typically the release of the carrier moiety should be rapid. Otherwise, it is desirable to utilize moieties that provide slow release, for example certain polymers or other moieties, for example cyclodextrins (see, for example, Cheng et al., Incorporated herein by reference). See US Patent Publication No. 20040077595, Application No. 10 / 656,838). Such carrier prodrugs are often advantageous for drugs for oral administration. In some cases, the transport moiety provides targeted delivery of the drug, for example the drug may be conjugated to an antibody or antibody fragment. Carrier prodrugs can be used, for example, to ameliorate one or more of the following features: increased lipophilicity, increased duration of pharmacological effect, increased site-specificity, reduced toxicity and adverse reactions and / or drugs Improvement of formulation (eg, stability, water solubility, undesirable sensory water solubility or inhibition of physicochemical properties). For example, lipophilic properties can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids, or esterification of carboxylic acid groups with alcohols such as aliphatic alcohols (see Wermuth supra). ).

Metabolites, eg, active metabolites, overlap with prodrugs described above, eg, bioprecursor prodrugs. Thus, such metabolites are pharmacologically active compounds or compounds that are further metabolized into pharmacologically active compounds, which are derivatives resulting from metabolic processes in a subject. Among them, active metabolites are such pharmacologically active derivative compounds. For prodrugs, prodrug compounds are generally inactive or less active than metabolites. In the case of active metabolites, the parent compound may be the active compound or may be an inert prodrug. For example, in some compounds, one or more alkoxy groups may be metabolized to hydroxyl groups while maintaining pharmacological activity and / or carboxyl groups may be esterified, eg, glucuronide. In some cases, there may be more than one metabolite in which the intermediate metabolite (s) are further metabolized to provide the active metabolite. For example, in some cases, derivative compounds resulting from metabolic gluconidation may be inactive or low in activity and may be further metabolized to provide active metabolites.

Metabolites of compounds can be identified using conventional techniques known in the art and their activity measured using tests such as those described herein. See, eg, Bertolini et al., 1997, J. Med . Chem . , 40: 2011-2016, Shan et al., 1997, J Pharm Sci 86 (7): 756-757; Bagshawe, 1995, Drug Dev . Res . , 34: 220-230; See Wermuth, supra.

Tautomers

It is contemplated that some compounds may exhibit tautomerism. In such cases, the formulas provided herein depict only one of the possible tautomeric forms. Accordingly, it is to be understood that Compound I provided herein is intended to represent any tautomeric form of the depicted compounds and is not intended to be limited to only the specific tautomeric forms depicted by the compound diagram.

Pharmaceutically acceptable salts

Unless stated to the contrary, the specification of Compound I herein includes pharmaceutically acceptable salts of such compounds. Thus, compound I may be in the form of a pharmaceutically acceptable salt or may be formulated into a pharmaceutically acceptable salt. Pharmaceutically acceptable salt forms contemplated include, without limitation, mono, bis, tris, tetrakis and the like. Pharmaceutically acceptable salts are nontoxic at the concentrations and amounts administered. The preparation of such salts can facilitate the physiological use by altering the physical properties of the compound without interfering with exerting a physiological effect. Useful modifications of physical properties include lower melting points to facilitate transmucosal administration and increased solubility to facilitate administration of higher concentrations of drug. Compound I has a sufficiently acidic and sufficiently basic functional group and can therefore react with a number of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts.

Pharmaceutically acceptable salts are acid addition salts such as chloride, bromide, iodide, hydrochloride, acetate, dichloroacetate phenylacetate, acrylate, ascorbate, aspartate, benzoate, 2-phenoxy Benzoate, 2-acetoxybenzoate dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, bicarbonate, butyne-1,4-dioate, hexine-1,6-dioate, capro Ate, caprylate, chlorobenzoate, cinnamate, citrate, decanoate, formate, fumarate, glycolate, gluconate, glucrate, glucuronate, glucose-6-phosphate, glutamate, hep Tanoate, hexanoate, isothionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate, lactate, malate, Maleate, hydroxymaleate, methylmaleate, malonate, mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate, oxalate, pamoate, phosphate, monohydrogen phosphate, Dihydrogenphosphate, orthophosphate, metaphosphate, pyrophosphate, 2-phosphoglycerate, 3-phosphoglycerate, phthalate, propionate, phenylpropionate, propiolate, pyruvate, quinate, salicylate Silates, 4-aminosalicylates, sebacates, stearates, suverates, succinates, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, sulfamate, sulfonates, benzenesulfonates (i.e. Besylate), ethanesulfonate (ie, oxylate), ethane-1,2-disulfonate, 2-hydroxyethanesulfonate (ie, isetionane) ), Methanesulfonate (ie mesylate), naphthalene-1-sulfonate, naphthalene-2-sulfonate (ie naphsylate), propanesulfonate, p-toluenesulfonate (ie tosylate), xylene Acid addition salts containing sulfonate, cyclohexylsulfate, tartrate and trifluoroacetate. Such pharmaceutically acceptable acid addition salts may be prepared using the appropriate acids of interest.

In the presence of acidic functional groups, for example carboxylic acids or phenols, pharmaceutically acceptable salts are also base addition salts, for example benzatin, chloroprocaine, choline, ethanolamine, diethanolamine, triethanolamine, t-butylamine, dicyclohexylamine, ethylenediamine, N, N'-dibenzylethylenediamine, meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine, procaine, aluminum, calcium Base addition salts, or amino acids, containing copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, ammonium, and mono-, di-, or tri-alkylamines (eg, diethylamine), Salts derived from, for example, L-histidine, L-glycine, L-lysine and L-arginine. For example, Remington's Pharmaceutical Sciences , 19 ^th ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995]. Such pharmaceutically acceptable base addition salts may be prepared using the appropriate corresponding base.

Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound can be isolated by dissolving in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid, and then evaporating the solution. In another example, salts can be prepared by reacting the free base and an acid in an organic solvent. If the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example by treatment of the free acid with the appropriate inorganic or organic base.

Other compound forms

In the case of solid phase agents, the compounds and salts are present in different crystal or polymorphic forms, or formulated in co-crystals, or in amorphous form, or in any combination thereof (eg, partially crystalline, partially It will be understood by those skilled in the art that these may be atypical, or a mixture of polymorphs, all of which are intended to be within the scope of the invention and as specified formulations. Salts are formed by acid / base addition, that is, the free base or free acid of the compound forms an acid / base reaction with the corresponding respective addition base or addition acid causing an ionic charge interaction, while co-crystal Is a novel chemical species formed between compounds of the same crystal structure and neutral compounds that result in additional molecular species.

In some cases, compound I is a base addition salt such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine, meglumine; Acid addition salts such as acetate, acetylsalicylate, besylate, camsylate, citrate, formate, fumarate, glutarate, hydrochlorate, maleate, mesylate, nitrate, oxalate, phosphate , Succinate, sulphate, tartrate, thiocyanate and tosylate; And acids including amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine Complexed by a base. In the combination of compound I with an acid or base, an amorphous complex is preferably formed rather than a crystalline material, for example a typical salt or co-crystal. In some cases, the amorphous form of the composite is facilitated by further processing, such as spray drying, mechanochemical methods such as roller compaction, or microwave radiation of the parent compound mixed with an acid or base. Such atypical complexes provide several advantages. For example, the lower melting point compared to the free base facilitates further processing, for example hot melt extrusion, further improving the biopharmaceutical characteristics of the compound. In addition, the amorphous composite is brittle to provide improved compression in the form of capsules or tablets in the form of solids.

In addition, compounds I or salts thereof described herein are intended to include hydrated or solvated forms as well as unhydrated or unsolvated forms of the defined materials. For example, compound I or salts thereof includes both hydrated and unhydrated forms. Other examples of solvates include structures combined with suitable solvents such as isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine.

Formulation  And administration

Compound I (including solid molecular complexes) described herein, or any form thereof, will typically be used to treat a human subject. However, Compound I and their compositions can also be used to treat similar or identical signs in other animal subjects, and can be used in injections (ie, parenterals including intravenous, abdominal, subcutaneous, and muscle), oral, transdermal, mucosal, It can be administered by different routes including rectal, or inhalation. Such dosage forms should allow the compound to reach the target cell. Other factors are well known in the art, and these factors include considerations, such as toxicity and dosage formulations that interfere with the compound or composition exerting its effect. Techniques and formulations can be commonly found in Remington: The Science and Practice of Pharmacy, 21 ^st edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005.

In some embodiments, a composition (including solid phase complexes disclosed herein) is a pharmaceutically acceptable carrier or excipient, such as fillers, binders, disintegrants, which may be selected to facilitate administration of a compound by a particular route, Lubricants, lubricants, complexing agents, solubilizing agents, and surfactants. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, starch type, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles and the like. Carriers also include, for example, sterile aqueous solutions for injection (WFI), saline, dextrose solution, Hanks' solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, and the like. Physiologically acceptable liquids for the suspension or as a solvent, including. Excipients include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethyl cellulose, crosslinked sodium carboxymethylcellulose, sodium benzoate , Calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, siloids, stearow C, magnesium oxide, starch, sodium starch glycolate, Glyceryl Monostearate, Glyceryl Dibehenate, Glyceryl Palmitostearate, Hydrogenated Vegetable Oil, Hydrogenated Cottonseed Oil, Castor Seed Oil, Mineral Oil, Polyethylene Glycol (e.g. PEG 4000 to 8000), Polyoxy Ethylene Recall, Poloxamer, Povidone, Crospovidone, Croscarmellose Sodium, Alginic Acid, Casein, Methacrylic Acid, Divinylbenzene Copolymer, Sodium Docusate, Cyclodextrin (e.g. 2-hydroxypropyl-delta-cyclodextrin ), Polysorbate (e.g. polysorbate 80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ether Polyethylene glycol Difatty acid esters, or polyoxyalkylene sorbitan fatty acid esters (eg, polyoxyethylene sorbitan esters Tween®), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, for example Sorbitan fatty acid esters, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried sucrose, fructose, calcium phosphate, dibasic calcium from fatty acids such as oleic acid, stearic acid or palmitic acid Phosphate, Tribasic Calcium Phosphate, Calcium Sulphate, Dextrate, Dextran, Dextrin, Dextrose, Cellulose Acetate, Maltodextrin, Simethicone, Polydextrosem, Chitosan, Gelatin, HPMC (hydroxypropylmethyl cellulose), HPC (Hydroxypropyl cellulose), hydroxy ethyl cellulose, hypromellose, etc. It may also be included.

In an embodiment of the invention, there is provided a formulation comprising the abovementioned solid phase suspension suspended in an aqueous vehicle. The formulation may further comprise colloidal silicon dioxide which has been found to stabilize the suspension. Silicon dioxide is preferably present in an amount of at least 0.5% by weight of the formulation. The aqueous vehicle is preferably about 2% by weight of hydroxypropyl cellulose.

In some embodiments, oral administration can be used. Pharmaceutical formulations for oral use may be formulated in conventional oral dosage forms such as capsules, tablets, and liquid formulations such as syrups, elixirs, and concentrated drops. Compound I may be combined with solid excipients, if desired, followed by blending with solid excipients, optionally milling the resulting mixture and processing the granule mixture, for example tablets, coated tablets, hard capsules, soft capsules, Solutions (eg, aqueous, alcoholic or oily solutions) and the like can be obtained. In particular, suitable excipients are fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol, cellulose preparations, for example corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum tragacanth), methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC) and / or polyvinylpyrrolidone (PVP: povidone); Oily excipients, including vegetable and animal oils such as sunflower oil, olive oil, or cod liver oil. Oral dosage forms include disintegrants such as crosslinked polyvinylpyrrolidone, agar, alginic acid, or salts thereof such as sodium alginate; Lubricants such as talc or magnesium stearate; Plasticizers such as glycerol or sorbitol; Sweetening agents such as sucrose, fructose, lactose, or aspartame; Natural or artificial flavors such as peppermint, wintergreen balm, or cherry flavors; Or dyes or pigments that may be used to identify or characterize different dosages or combinations. It also provides dragees with suitable coatings. To this end, it will optionally contain, for example, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Concentrated sugar solutions can be used.

Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin ("gelcaps") as well as sealed soft capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.

In some embodiments, injections (parenteral administration) can be used, such as intramuscular, intravenous, intraperitoneal and / or subcutaneous injections. Compounds I and their compositions for injection can be formulated in sterile liquid solutions, preferably in physiologically acceptable buffers or solutions such as saline, Hanks 'solution, or Ringus' solution. Dispersions can also be prepared in non-aqueous solutions such as glycerol, propylene glycol, ethanol, liquid polyethylene glycols, triacetin, and vegetable oils. The solution may also contain preservatives such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In addition, Compound I or compositions thereof can be formulated in solid form, including, for example, lyophilized forms, and redissolved or suspended prior to use.

In some embodiments, mucosal, topical or transdermal administration can be used. In such formulations of compound I, appropriate penetrants are used for the barrier to be permeated. Such penetrants are commonly known in the art and, for example, penetrants for mucosal administration contain bile hydrochloric acid and fusidic acid derivatives. In addition, detergents can be used to promote permeation. For example, mucosal administration may be via nasal spray or suppositories (rectal or vaginal). Compositions of Compound I for topical administration can be formulated in oils, creams, lotions, ointments and the like by selecting appropriate carriers known in the art. Suitable carriers include vegetable or mineral oils, white mineral oils (white soft paraffins), branched chain fats or oils, animal fats and high molecular weight alcohols (above C ₁₂ ). In some embodiments, the carrier is selected such that the active ingredient is soluble. If desired, emulsifiers, stabilizers, wetting agents and antioxidants as well as agents which impart color or odor may also be contained. The cream for topical application is preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water mixed with the active ingredient dissolved in a small amount of solvent (eg oil). In addition, the method of transdermal administration may comprise a transdermal patch or dressing, such as a bandage impregnated with the active ingredient and optionally one or more carriers or diluents known in the art. To be administered in the form of a transdermal delivery system, the dosage administration will be continuous rather than intermittent through the dosage regimen.

In some embodiments, Compound I or a composition thereof is administered as an inhalant. Compound I or a composition thereof can be formulated as a dry powder or a suitable solution, suspension, or aerosol. Powders and solutions can be formulated with suitable additives known in the art. For example, the powder may contain a suitable powder base such as lactose or starch, and the solution may include propylene glycol, sterile water, ethanol, sodium chloride and other additives such as acids, alkalis and buffer salts. have. Such solutions or suspensions may be administered by inhalation via spraying, pumps, nebulizers, nebulizers, and the like. Compound I or a composition thereof may also be used for other inhalational treatments such as corticosteroids such as fluticasone proprionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone. Furoate; Beta agonists such as albuterol, salmeterol, and formoterol; Choline inhibitors such as ifpratroprium bromide or tiotropium; Vasodilators such as treprostinal and iloprost; Enzymes such as DNAase; Therapeutic protein; Immunoglobulin antibodies; Oligonucleotides such as single or double helix DNA or RNA, siRNA; Antibiotics such as tobramycin; Muscalinic receptor antagonists; Leukotriene antagonists; Cytokine antagonists; Protease inhibitors; Chromoline sodium; Nedocryl sodium; And sodium chromoglycate.

The amount of Compound I or a composition thereof to be administered may be determined by factors such as, for example, compound activity (in vitro, for example Compound IC ₅₀ versus target, or in vivo activity in an animal efficacy model), pharmacokinetic results in an animal model (e.g. Biological half-life or bioavailability), age, size and weight of the subject, and disorders associated with the subject may be determined by standard procedures. The importance of these and other factors is well known to those skilled in the art. Typically, the dosage will range from about 0.01 to 50 mg, and also from about 0.1 to 20 mg per kg of the subject to be treated. Multiple doses can be used.

Compound I or a composition thereof can also be used in combination with other therapies to treat the same disease. Such combination use includes administering Compound I and one or more other therapeutic agents at different times, or co-administering Compound I and one or more other therapeutic agents. In some embodiments, dosages for Compound I or other therapeutic agents used in combination can be altered, eg, relative to a compound or therapeutic agent used alone, by methods well known to those of ordinary skill in the art, You can.

Use in combination includes use with other therapies, drugs, medicinal procedures, and the like, wherein the other therapies or procedures are performed at a different time (eg, within a shorter time, for example, hours, than Compound I or their compositions). (Eg, within 1, 2, 3, 4 to 24 hours) or longer time (eg, 1 to 2 days, 2 to 4 days, 4 to 7 days, 1 to 4 weeks), Or a compound I or a composition thereof. Use in combination refers to the use of a therapeutic or medicinal procedure, such as the use of Compound I or a composition thereof, which administers a single or infrequent procedure, eg, surgery, within a short time or longer time before or after another treatment or procedure. Also includes. In some embodiments, the present invention provides for the delivery of Compound I or a composition thereof and at least one other drug therapy delivered by a different route of administration or by the same route of administration. The use of any route of administration in combination may include any formulation, including formulations in which the two compounds are chemically bound in such a way as to deliver Compound I or a composition thereof and maintain their therapeutic activity upon administration of both compounds. At least one other drug therapy delivered together by the same route of administration. In one aspect, the other drug treatment may be co-executed with Compound I or a composition thereof. Combination use by co-implementation can be accomplished by administering a co-formulation or formulation of a chemically bound compound, or by placing two or more compounds in separate formulations together for a short time (e.g., 1 hour, 2 hours, 3 hours, up to 24 hours), by the same or different routes of administration. Co-administration of separate formulations includes co-administration via one device, eg, the same inhalation device, the same syringe, or the like, or from separate devices within a short time. Co-formulations of Compound I and one or more additional drug therapies delivered in the same route allow for the administration of them together in one formulation while maintaining the separate compounds or their biological activity so that they can be administered together by one device Preparing these materials, including compounds modified to be chemically bound. Such chemically bound compounds may have a bond that is substantially retained in vivo or that can be degraded in vivo to separate the two active components.

Example

Examples relating to the present invention are described below. In most cases, alternative techniques can be used. The following examples are for illustrative purposes and do not limit or limit the scope of the invention.

Example  One

This example describes the formation of a solid phase molecular complex comprising Compound I and HPMC-AS.

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide And HPMC-AS were dissolved in dimethylacetamide (DMA) in a ratio of 3: 7 (30% compound and 70% polymer). The resulting solution was then added to very cold diluted hydrochloric acid with stirring to produce propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbox Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo as a solid phase molecular complex in which carbonyl] -2,4-difluoro-phenyl} -amide is present in the nanoparticulate size range [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide and HPMC-AS were co-precipitated. The ratio of DMA to acid ranged from 1: 5 to 1:10. The co-precipitate was then washed with water to remove DMA, filtered, dried to less than 2% moisture content and passed through a # 30 mesh screen before evaluation. The resulting solid phase molecular complex comprises 30% by weight of propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2, 4-difluoro-phenyl} -amide and 70% by weight of HPMC-AS.

The properties of the resulting solid phase molecular complexes were as follows.

Example  2 to 7

Solid phase molecular complexes comprising Compound I and HPMC-AS were prepared using a method analogous to that used in Example 1 to provide propane-1-sulfonic acid {3- [5- (4-chloro-phenyl)-in the solid phase molecular complexes. The ratio of the amount by weight of 1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide to the amount by weight of the ionic polymer is 3: 7, respectively. , 5: 5, 5: 5, 4: 6, 4: 6 and 2: 8 to prepare solid-state molecular complexes.

The amorphous state of the solid-state molecular complexes prepared in Examples 1 to 7 was evaluated by powder XRD. Samples were placed under open (OPEN) conditions by placing the samples in bottles in a stable chamber without lids or lids or plugs at 40 ° C. and 75% relative humidity (RH), after which the properties of the solid phase molecular complexes were observed. The exposure period is shown in the table below. At the end of the exposure period, a powder sample was taken from the bottle and placed in a powder X-ray diffraction (XRD) chamber to obtain a diffraction pattern. The sample was considered stable if the powder XRD profile did not show a crystalline peak. Samples prepared and stored were also evaluated by polarizing microscope. If crystals were present in the sample, the generation of polarization caused a birefringence phenomenon. For atypical samples, these tests could indicate the presence of crystalline material indicating that the amorphous material is unstable.

Example  8

This example provides propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro- Formation of solid phase molecular complexes comprising phenyl} -amide and Edragit® L 100 has been described. Edragit L 100 was another anionic polymer that was a polymethyl methacrylate ester with methacrylic acid as a functional group and was dissolved above pH 6.0.

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide And edragit L 100 were dissolved in dimethylacetamide (DMA) in a ratio of 3: 7 (30% compound and 70% polymer). The resulting solution was then added to very cold diluted hydrochloric acid with stirring to provide propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pi as a solid phase molecular complex in which the drug was present in the nanoparticulate size range. Rolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide and edragit L 100 were co-precipitated. The co-precipitate was then washed with water to remove DMA, filtered, dried and milled into fine powder. The ratio of DMA to acid ranged from 1: 5 to 1:10. The co-precipitate was then washed with water to remove DMA, filtered, dried to less than 2% moisture content and passed through a # 30 mesh screen before evaluation. The resulting solid phase molecular complex comprises 30% by weight of propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2, 4-difluoro-phenyl} -amide and 70% by weight of edragit L 100.

Immediately after preparation, the amorphous state of the solid phase molecular composite sample was evaluated with powder XRD. Samples were stored under open conditions for various time periods similar to those shown in Examples 1-7 at 40 ° C./75% RH. At the end of the exposure period, a powder sample was taken from the bottle and placed in a powder X-ray diffraction (XRD) chamber to obtain a diffraction pattern. The sample was considered stable if the powder XRD profile did not show a crystalline peak. Samples prepared and stored were also evaluated by polarizing microscope. If crystals were present in the sample, the generation of polarization caused a birefringence phenomenon. For atypical samples, these tests could indicate the presence of crystalline material indicating that the amorphous material is unstable. The results of this example are shown in Table 2 below.

Example  9

This example provides propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro- Phenyl} -amide and Edragit® L 100 were dissolved in dimethylacetamide (DMA) in the ratio of 4: 6 (40% compound and 60% polymer) instead of 3: 7 of Example 8. Was carried out in the same steps as in Example 8. The results of this example are shown in Table 2 below.

Example  10

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl]-using a microprecipitation process in the same manner as in Example 1 Solid phase molecular complexes containing 2,4-difluoro-phenyl} -amide and edragit L 100-55 in ratios of 4: 6 and 5: 5, respectively, were formed. Edragit L 100-55 dissolves at pH 5.5 and above, thus similar to L 100 except that its pH solubility profile is very closely similar to HPMC-AS. Prepared and stored samples were evaluated by powder XRD. The results of this example are shown in Table 2 below.

Example  11

This example provides propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro- Formation of solid phase molecular complexes comprising phenyl} -amide and another anionic polymer, hydroxypropylmethylcellulose phthalate (HPMCP), used for enteric purposes has been described. HPMCP was a cellulose polymer in which some of the hydroxyl groups, 27-35%, were replaced with phthalyl esters. The polymer began to dissolve above pH 5.5. Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl]-using the same method as used in Example 1 Solid phase molecular complexes containing 2,4-difluoro-phenyl} -amide and HPMCP in a ratio of 1: 1 were prepared. Prepared and stored samples were evaluated by XRD. The results of this example are shown in Table 2 below.

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4- according to Examples 1-11. A 4: 6 ratio of difluoro-phenyl} -amide to polymer showed the highest drug loading (40%) sustainable when stored with HPMC-AS as a polymer. Therefore, this ratio was chosen in a separate study unlike other polymers.

Examples 12-16 were prepared by a microprecipitation process similar to Example 1. Immediately after preparation, amorphous X of the dry powder sample was evaluated with powder XRD. The samples were also stored under open conditions for various periods at 40 ° C./75% RH similar to those shown in Examples 1-7. The results are shown in Table 3 below.

Example  12

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide And solid phase molecular complexes containing HPMC-AS in a ratio of 4: 6 were observed to be amorphous immediately after preparation (Table 3) and stored for 4 weeks at 40 ° C./75% RH.

XRD of the solid phase molecular complex was evaluated.

Example  13

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide And solid phase molecular complexes containing HPMCP in a ratio of 4: 6 were observed to be amorphous immediately after preparation (Table 3) and stored for 4 weeks at 40 ° C./75% RH.

Example  14

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide And solid phase molecular complexes containing Edragit L 100-55 in a ratio of 4: 6 were observed to be amorphous immediately after preparation (Table 3) and stored for 4 weeks at 40 ° C./75% RH.

Example  15

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide And solid phase molecular complexes containing polyvinylacetate phthalate (PVAP) in a ratio of 4: 6 were crystalline immediately after preparation and therefore no further tests were performed. PVAP was an anionic enteric polymer formed from phthalate esters of polyvinyl acetate and contained 55-62% phthalyl groups. PVAP had a low Tg of 42.5 ° C. which was unsuitable as a stabilizing polymer matrix. It was dissolved at a pH above 5.

Example  16

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide And solid phase molecular complexes containing cellulose acetate phthalate (CAP) in a ratio of 4: 6 were crystalline immediately after preparation and therefore no further tests were performed.

The powder XRD profiles of Examples 12-16 in the initial stage immediately after preparation are shown in Table 3.

After 1 week, the sample prepared under Example 13 showed a small peak indicating conversion to crystalline form in powder XRD. This peak became more pronounced after two weeks of storage.

Example  17

The samples prepared in Examples 12 and 14 did not show any crystalline peaks in the powder XRD profile after up to 4 weeks storage.

To further distinguish the samples of Examples 12 and 14, 80 mg of propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H- was added to a USP Paddle dissolution apparatus at a speed of 75 rpm. The solid phase molecular complex in an amount corresponding to pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide was added at a pH of 900 mL containing 0.09% HTAB surfactant. 6.8 Dissolution testing of the samples was performed by placing in phosphate buffer medium.

In one set of experiments, a # 25/40 mesh sieve size fraction was separated to obtain a sieve cut of the granules of Examples 12 and 14 and a dissolution test. The HPMC-AS solid-state molecular complex was dissolved about 85% at 200 minutes and the Edragit L 100-55 solid-state molecular complex was dissolved at about 40% in 200 minutes, compared to the HPMC-AS solid-state molecular complex. The amount of dissolution (%) of the solid phase molecular complex was increased.

In another experiment, the solid phase molecular complex samples of Examples 12 and 14 were pre-soaked with a vehicle containing hydroxypropyl cellulose (Klucel) for improved dispersion and dissolution testing was performed. HPMC-AS solid-state molecular complexes were dissolved about 60-65% in 200 minutes and edragit L 100-55 solid-state molecular complexes were dissolved in about 20 to 25% in 200 minutes, resulting in edragit L 100-55 solid-state molecular complexes. In comparison, the dissolution amount (%) of the HPMC-AS solid-state molecular complex was increased.

As a result of these experiments, HPMC-AS not only stabilizes the drug when stored under stress conditions but also allows drug release, atypical drug does not return to crystalline form during dissolution within test period and maintains supersaturation of atypical drug It was an excellent polymer. Since Edragit L 100-55 did not enhance drug release compared to HPMC-AS, it was not thought that it would provide exposure and bioavailability like HPMC-AS. At the end of 3 hours, nearly 90% of the drug was released from Example 12 (HPMC-AS), while Example 14 (Edragit L-100-55) only released about 50% of the drug. Thus, propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4 prepared by a microprecipitation process -Difluoro-phenyl} -amide and HPMC-AS solid-state molecular complexes not only stabilize amorphous compounds during handling and storage, but also ensure rapid drug release, resulting in good dissolution and thus bioavailability.

Example  18

This example demonstrates stabilization of solid phase molecular complexes in aqueous systems. The solid phase molecular complex of drug-HPMC-AS was suspended in an aqueous vehicle containing 2% hydroxypropylcellulose (Klucel LF). When the colloidal silicon dioxide was added in excess of 0.5% w / w, it was observed that the resulting suspension was stable for up to 8 hours under normal conditions and for up to 24 hours under cooling conditions.

Example  19

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Can be present in polymorphic form, for example polymorphic form 1 or 2, and such polymorphic forms could be isolated as substantially pure polymorphs. The desired polymorphic form could be prepared, for example, using appropriate crystallization conditions. For example, Form 1 was isolated by recrystallization from acetone / anhydrous ethanol (eg, 1: 1 to 5: 1, preferably 2: 1 volume ratio) as detailed herein. Form 2 may be formed directly, for example, via crystallization from dimethylacetamide / methanol or under various recrystallization conditions, for example recrystallization from methyl-t-butyl ether / tetrahydrofuran, ethyl acetate, acetone Or a mixture of any solid form or solid form, such as Polymorph Form 1, by heating / melting and restocking. Substantially pure isolated polymorphic forms were characterized by x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared spectroscopy (see Example 20 below).

To demonstrate the formulation of Polymorph Form 1, propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1 H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2 , 4-Difluoro-phenyl} -amide (7.8 kg) was treated in the reactor with acetone: anhydrous ethanol (1: 4 volume ratio, 19 kg) and stirred at 20 ° C ± 5 ° C for at least 6 hours. The contents were filtered and the solids were washed with acetone: anhydrous ethanol (1: 4 volume ratio) mixture. After treating the solid with tetrahydrofuran (26.6 kg), the suspension was heated to 60 ° C. ± 5 ° C. for at least 30 minutes and stirred. The mixture was cooled to 55 ° C. ± 5 ° C. and methyl-t-butyl ether (92.3 kg) was added. The resulting suspension was cooled to 20 ° C ± 5 ° C for at least 1 hour. After filtering the contents the solid was washed with methyl-t-butyl ether and dried. The solids were treated with acetone: anhydrous ethanol (2: 1 volume ratio) in the reactor. The contents were stirred and the suspension was heated to 60 ° C. until a solution was obtained. The solution was filtered through a large abrasive filter to remove any residual solids from the methyl-t-butyl ether treatment step. The filtrate was concentrated under vacuum and stirred at 20 ° C. ± 5 ° C. for 30 minutes and then filtered. The solids were washed with precooled (0 ° C. to −5 ° C.) ethanol, dried at 45 ° C. and dried at 75 ° C. under vacuum until constant weight was obtained to obtain pure propane-1-sulfonic acid {3- [5- ( 4-Chloro-phenyl) -1 H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide polymorph Form 1 was obtained. Form 1 was also prepared by treating the sample with 120 mL of acetone: ethanol (1: 1 volume ratio) under reflux, then hot filtration and removing the solvent from the filtrate under vacuum until a solid precipitated out.

Example  20

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Polymorph Form 1 and Form 2 were characterized by powder x-ray diffraction, infrared spectroscopy and differential scanning calorimetry. Samples were analyzed by x-ray powder diffraction (XRPD) using a Shimadzu XRD-6000 x-ray powder diffractometer using Cu Kα radiation. Tube voltage and amperage number were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set to 1 ° and the light receiving slit was set to 0.15 mm. Diffraction radiation was detected with a NaI scintillation detector. Continuous scans of θ to 2θ were used at 3 ° / min (0.4 seconds / 0.02 ° steps) from 2.5 ° to 40 ° 2θ. Silicon standards were analyzed to check the machine arrangement. Data was collected and analyzed using XRD-6100 / 7000 v.5.0. Samples were placed for analysis by placing them inside an aluminum holder with a silicon insert. The results are provided in FIGS. 1 (Form 1) and 2 (Form 2) and Table 4 below.

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Polymorph Form 1 and Form 2 were further analyzed by infrared spectroscopy. Table 5 provides the characteristic wave numbers observed for each sample.

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Polymorph Form 1 and Form 2 were also analyzed by differential scanning calorimetry (DSC) and scanned at 10.00 ° C. per minute. DSC thermal analysis for Form 1 showed exothermic shifts at approximately 152-164 ° C. and endothermic peaks at 268.0 ° C. DSC thermogram for Form 2 showed endothermic peak at 271.2 ° C.

Example  21

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide Has been characterized as having the function of providing both weak bases and weak acid centers that can form organic salt complexes that result in improved solubility. For example, the portion of azaindole of N-7 is a weak base (pKa is approximately 4-5) and the acid addition salt complex is combined with an organic acid such as benzenesulfonic acid, methylsulfonic acid or toluenesulfonic acid, preferably methanesulfonic acid or toluenesulfonic acid. Could form. Such mesylate or tosylate salts have provided advantages over free base, such as improved solubility, improved intrinsic dissolution rate and lower melting point than free base. The improved intrinsic dissolution rate provided the advantage of the formulation of the salts, eg, in amorphous form, by the methods described in the above examples. Improved solubility provides a more efficient and cost effective formulation, for example spray drying or microprecipitation bulk processes could be performed using much less solvent volumes due to inherent solubility. Such an advantage could also be provided by forming mesylate or tosylate salts in situ during the process, for example during spray drying, solvent controlled precipitation, pH controlled precipitation. In addition, lower melting in the form of salts provided a more efficient hot melt extrusion process in which the melt could be processed at lower temperatures.

Preferably, propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1 H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro- Acid addition salts of phenyl} -amide (including a series of organic anionic sulfonic acids such as tosylate, besylate or mesylate) were formed by dissolving the free base and using acetone rather than solvent once the salt was formed. Typically, propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1 H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl } -Amide was added to acetone in a solvent volume of 20-50 times with stirring and heating (30-35 ° C.), followed by 1 equivalent of the desired acid counter ion. The solution was slowly cooled to 2-8 ° C. and the solid was isolated by filtration or centrifugation and dried in vacuo. The resulting solids can be amorphous, partially amorphous or crystalline and can be recrystallized from alcohol: acetone: ethyl acetate or only alcohol as needed to give the desired solid in crystalline form.

Propane-1-sulfonic acid {3- [5- (4-chloro-phenyl) -1H-pyrrolo [2,3-b] pyridine-3-carbonyl] -2,4-difluoro-phenyl} -amide The mesylate salt of was prepared by suspending 5 g (9.7 mmol) of Polymorph Form 2 in 100 ml of acetone and mixing with heating to 30 to 35 ° C. Methanesulfonic acid (0.63 mL, 9.7 mmol) was added and then the solution was cooled to 5 ° C. over 30 minutes. The resulting solid was isolated by filtration, washed and dried under vacuum to afford the desired salt. Tosylate salts were prepared similarly. Representative XRPD patterns for the mesylate and tosylate salts are provided in FIGS. 3 and 4, respectively, compared to free base polymorph Form 2. DSC thermogram for mesylate salt showed an endothermic peak at approximately 231 ° C. DSC thermal analysis of the tosylate salt showed an endothermic peak at approximately 223 ° C. and another endothermic peak at approximately 253 ° C.

The resulting salts can be processed via the techniques discussed in the examples above, for example, by spray drying, solvent controlled precipitation, pH controlled precipitation or hot melt extrusion to provide the desired amorphous form or further processing with suitable excipient materials directly Provided are compressible or encapsulated dosage forms. The salt form has the advantage of not only obtaining a construct not obtainable using conventional solvent techniques in the process, but also minimizing solvent use, for example, and increasing yield, purity and throughput.

Example  22

This example describes the preparation of a solid dispersion (MBP) of amorphous Compound I in HPMCAS.

DMA  Tops:

The concentration of compound I and HPMCAS in the organic solvent was 35% (w / w) and the ratio of compound I and HPMCAS was 30 to 70. The temperature of the solution was adjusted to 70 ° C.

In a 250 ml double jacketed glass flask reactor, 21 g of compound I was dissolved in 130 g of dimethylacetamide (DMA) at 20-25 ° C. 48.9 g of HPMC-AS was added to this solution with stirring. The mixture was heated up to 70 ° C. A clear solution was obtained.

Preparation of the aqueous phase

In a double jacket 2.0 liter reactor as illustrated in FIG. 5, 1210 g of 0.01 N HCl was adjusted to 5 ° C. Using a high shear mixer or auxiliary pump, preferably a rotary lobe pump, the aqueous phase was circulated out of the bottom valve of the reactor and then returned to the high shear mixer and then to the top of the reactor. The inlet of recycle to the reactor was placed below the fluid level to prevent foaming (see FIG. 5).

Sedimentation

High shear  Mixer ( HSM )

The tip speed of the rotor in the high shear mixer was set to 25 m / sec. Rotor / stator combinations with one tooth row each of the rotor and stator were used.

DMA  Administration of the solution

Using a gear pump, the DMA solution adjusted to 70 ° C. was administered into the circulating aqueous phase through the injector nozzle directed into the mixing chamber of the high shear mixer.

DMA  Dose rate of the solution

The DMA solution was administered to the aqueous phase, resulting in a ratio of HCl / DMA of 100/1 in the mixing chamber of the high shear mixer.

(After settling) HSM Dispersion, isolation and washing in

After addition of the DMA solution, the MBP suspension obtained was dispersed for an additional time, to correspond to the equivalent of the batch through the high shear mixer. The time corresponded to the conversion at the calculated recycle time of six times the batch.

The resulting suspension, maintained at 5-10 ° C., was separated from solid MBP. This was done using a suction filter. Isolated MBP was washed with 0.01 N HCl (15 kg 0.01 N HCl / kg MBP) followed by water (5 kg water / kg MBP) to remove DMA. Isolated (wet) MBP had a water content of 60 to 70%.

Dismantling and drying

(Wet) MBP was disassembled using a sieve mill before drying. (Wet) MBP was dried in a cabinet drier. The temperature of the product was below 40 ° C. to prevent recrystallization of the API during the drying process of MBP. The cabinet dryer internal pressure was less than 20 mbar. After drying, the water content of MBP was less than 2.0% and showed atypical in the XRPD pattern.

Example  23

This example describes spray dried formulations of solid phase molecular complexes comprising Compound I and HPMC-AS.

Compound I is a surfactant (e.g., sodium, 1,4-bis (2-ethylhexoxy) -1,4-dioxobutane-2-sulfonate (docuate sodium) or poly Nonionic surfactants such as Solvate 80). Generally, a suitable solvent system, for example 20:80 (w / w) tetrahydrofuran: acetone, is equilibrated to 30 ° C. and divided 4 to 6 times to add compound I with stirring to the level of 2 to 10% solids. It was. HPMCAS was added at a suitable ratio such as 70:30 w / w HPMCAS: Compound I (alternatively, for example 65: 5: 30 HPMCAS: Surfactant: HPMCAS of Compound I and surfactant). The temperature was raised to 35-40 ° C. and the system was optionally filtered to ensure removal of any insoluble solids. The solution was then spray dried to give spherical particles having a size distribution of 1-20 μm. Further processing may include drying of the material in a fluidized bed or tray dryer, and the resulting material may be compacted, for example by roller compaction. As an example, 30:70 (w / w) ratio of Compound I and HPMCAS were dissolved at a solids level of 5.4% in a blend of 20:80 (w / w) tetrahydrofuran and acetone. The resulting solution was then spray dried to produce a solid dispersion, amorphous powder. Use this solution in a suitable spray dryer, eg GEA-Niro SDM _ICRO ™ Spray Dryer for small batches (eg 10 g solids) and Niro Mobile Manor for large batches (eg 1 kg solids) Spray dried using a spray dryer. For example, for a 10 g batch, 35.0 g of tetrahydrofuran is mixed with 140.0 g of acetone in a glass beaker, 3.0 g of compound I is added with stirring for 10 minutes to dissolve, followed by 7.0 g of HPMCAS- L (Shin-Etsu Grade NF) was added and stirred. The solids appeared to dissolve but the solution was filtered through filter paper prior to spray drying. The solution was spray dried using a GEA-Niro SDM _ICRO ™ spray dryer at a spray gas pressure of 0.5 bar and inlet / outlet conditions of 85 ° C. and 55 ° C., respectively. Spray dried material was collected in a cyclone collector. 5.78 g or 58% yield.

A 1.6 kg batch was also prepared, wherein the solution was prepared similarly, but instead of filtration, the solution was stirred overnight at room temperature to allow all solids to dissolve. A 200 mesh screen was attached to the feed hose end to remove any undissolved particles and the solution was spray dried using a Mobile Manor spray dryer. Inlet / outlet conditions were 100 ° C. and 55 ° C., spray gas pressure was 1.0 bar and gas flow rate was 90 kg / hr. The material was spray dried for 2 days and the collected material was vacuum dried at 45 ° C. after the first day to remove residual solvent. Bulk density (0.23 g / mL) of collected material, particle size (8 μm of normal distribution and standard deviation of 3 μm), residual solvent (after 89 hours vacuum drying, large batches of 0.001% acetone and 0.017% tetrahydrofuran Solvent remaining), polarization microscope, DSC (DSC thermal analysis on small batches showed endothermic peaks at approximately 243 ° C., while thermal analysis on large batches essentially did not show any peaks) and XRPD ( Measured amorphous material).

All patents and other references cited in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains, including any tables and figures, to the same extent that each reference is individually incorporated by reference in its entirety. The entirety of which is incorporated herein in its entirety.

Those skilled in the art will readily recognize that the present invention is sufficiently adapted to obtain the objects and advantages mentioned as well as those inherent therein. The methods, modifications, and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Those skilled in the art will recognize variations and other uses as defined by the scope of the claims and included within the spirit of the invention.

It will be readily apparent to those skilled in the art that various permutations and modifications can be made to the invention disclosed herein without departing from the scope and spirit of the invention. For example, crystallization or co-crystallization conditions for Ret can be modified and Let surrogate proteins and / or various kinase domain sequences can be used. Accordingly, such additional embodiments are within the scope of the invention and the following claims.

The invention described by way of example herein may suitably be practiced in the absence of any element or elements, limitation or limitations not expressly disclosed herein. Thus, for example, in each case herein any one of the terms "comprising", "consisting essentially of" and "consisting of" may be replaced by two other terms. Thus, for embodiments of the present invention using one of the above terms, the present invention also includes another embodiment in which one of the above terms is replaced by another of these terms. In each embodiment, the terms have their established meanings. Thus, for example, one embodiment may comprise a method comprising “a series of steps” and another embodiment will include a method “consisting essentially of” a same step, and a third embodiment may comprise It will include methods "consisting of" in the same steps. The terms and expressions used are used as terms of description, not limitation, and the use of such terms and expressions is not intended to exclude any equivalents or portions thereof of the features presented and described, and various modifications of the present invention are claimed. It should be recognized that it is possible within the scope. Thus, while the present invention has been specifically disclosed herein as the preferred embodiment, any features, modifications, and variations of the concepts disclosed herein will be apparent to those skilled in the art and such variations and changes are as defined by the appended claims. It is considered to be within the scope of the present invention.

In addition, where features or aspects of the invention are described in the Markush group or alternative groups, those skilled in the art will also describe the invention as any individual element or subgroup of elements of the Markush group or other groups. It will be recognized.

Also, unless stated to the contrary, additional embodiments are described by taking any two different values as end points of a range, provided that various numbers of values are provided in the embodiments. Such ranges are also within the scope of the described invention.

Accordingly, further embodiments are within the scope of this invention and the following claims.

Claims (50)

A solid phase dispersion comprising Compound I dispersed molecularly in a polymer matrix formed by an ionic polymer in a solid state. The solid phase dispersion of claim 1, wherein the ionic polymer is selected from the group consisting of hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate and methacrylic acid copolymer. The solid phase dispersion of claim 2, wherein the ionic polymer is selected from the group consisting of hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose and methacrylic acid copolymers. The solid phase dispersion according to any one of claims 1 to 3, wherein the polymer is hydroxypropylmethyl cellulose acetate succinate (HPMCAS). The solid phase dispersion according to any one of claims 1 to 3, wherein the polymer comprises methacrylic acid copolymer. The solid phase dispersion of claim 1, wherein the polymer comprises EUDRAGIT® L 100-55. The solid phase according to any one of claims 1 to 6, wherein the ratio of the weight-based amount of compound I in the solid phase dispersion to the weight-based amount of the ionic polymer in the solid phase dispersion is from about 1: 9 to about 1: 1. Dispersion. The solid phase according to any one of claims 1 to 7, wherein the ratio of the weight basis amount of compound I in the solid phase dispersion to the weight basis amount of the ionic polymer in the solid phase dispersion is from about 2: 8 to about 4: 6. Dispersion. The solid phase dispersion according to claim 1, wherein the ratio of the weight basis amount of compound I in the solid dispersion to the weight basis amount of the ionic polymer in the solid dispersion is about 3: 7. 10. 10. The solid phase dispersion according to claim 1, wherein compound I is in predominantly amorphous form. The solid phase dispersion of claim 4, wherein hydroxypropylmethyl cellulose acetate succinate (HPMCAS) is present in an amount of at least about 20% by weight of the solid phase dispersion. The solid phase dispersion of claim 11, wherein the hydroxypropylmethyl cellulose acetate succinate is present in an amount from about 20% to about 95% by weight of the solid phase dispersion. The solid phase dispersion of claim 11, wherein the hydroxypropylmethyl cellulose acetate succinate is present in an amount from about 20% to about 70% by weight of the solid phase dispersion. 14. A composition comprising a solid dispersion according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier. A formulation comprising a solid dispersion according to any one of claims 1 to 13 or a composition according to claim 14 suspended in an aqueous vehicle. The formulation of claim 15 further comprising colloidal silicon dioxide. The formulation of claim 16, wherein the colloidal silicon dioxide is present in an amount of at least 0.5% by weight of the composition. 18. The formulation according to any one of claims 15 to 17, wherein the aqueous vehicle contains 2% by weight of hydroxypropyl cellulose. 14. A process for the preparation of the solid phase dispersion according to any one of claims 1 to 13 comprising microprecipitation of compound I and the ionic polymer. The method of claim 19, wherein compound I and the ionic polymer are precipitated simultaneously to form a molecular dispersion of compound I in the ionic polymer. The method of claim 19, wherein the solid dispersion is prepared by spray drying. The method of claim 19, wherein the solid dispersion is prepared by hot melt extrusion. The method of claim 19 comprising the process step of solvent controlled precipitation. 24. The method of any one of claims 19-23, wherein the polymer is hydroxypropylmethyl cellulose acetate succinate. The method of claim 24, wherein compound I and hydroxypropylmethyl cellulose acetate succinate are dissolved in an organic solvent. The method of claim 25, wherein the solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, dimethyl sulfoxide and N-methyl pyrrolidone. 27. A solid phase molecular composite according to claim 25 or 26, wherein compound I and hydroxypropylmethyl cellulose acetate succinate are precipitated simultaneously by adding the resulting solution to water to contain compound I sandwiched in a matrix formed of said polymer. How to form. 27. Compound I according to claim 25 or 26, wherein the resulting solution is added to aqueous hydrochloric acid (HCl) to simultaneously precipitate compound I and hydroxypropylmethyl cellulose acetate succinate to contain compound I intercalated in a matrix formed of said polymer Forming a solid-state molecular complex. 29. The method of any one of claims 19-28, wherein the resulting solid phase molecular complex is washed with water to remove the organic solvent. 20. The method of claim 19,
(a) dissolving Compound I and HPMCAS in the same organic solvent to form one single organic phase,
(b) The organic phase obtained in step (a) is continuously added to the aqueous phase present in the mixing chamber equipped with two additional openings connecting the mixing chamber to the closed loop and the high shear mixing device, wherein the aqueous phase Circulating and passing through the mixing chamber,
(c) While the high shear mixer is in operation and the aqueous phase is passed through the mixing chamber in a closed loop, the mixture consisting of HPMCAS and the amorphous form of compound I from the aqueous phase mentioned in step (b) is precipitated to form an aqueous suspension of the precipitate. Steps,
(d) The organic solution prepared in step (a) is completely added during the operation of the high shear mixing apparatus and until the defined particle size and / or particle size distribution is obtained, and then the aqueous suspension is added to the mixing chamber. Continuously cycling to,
(e) isolating the solid phase from the suspension,
(f) washing the isolated solid phase with water, and
(g) delumping and drying the solid phase. The method of claim 30,
The organic phase in step (a) is a 35% solution of compound I and HPMCAS in DMA with a ratio of compound I to HPMCAS of 30% to 70% (w / w),
The continuous addition in step (b) is about 1 to about 10 mm away from the rotor of the high shear mixer operating at a tip speed of about 15 to about 25 m / sec and with respect to the longitudinal axis of the high shear mixer The method is carried out through an injector nozzle oriented at a 40 to 50 ° angle. Crystalline polymorphic form of Compound I showing a powder x-ray diffraction pattern with characteristic peaks of 2θ at approximately 4.7, 9.4, 11.0, 12.5, and 15.4 ° positions. 33. The crystalline polymorph of claim 32, wherein the crystalline polymorph exhibits a powder x-ray diffraction pattern having characteristic peaks of 2θ at approximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 18.6, and 22.2 degrees. 33. The crystalline polymorph of claim 32, wherein the crystalline polymorph exhibits a powder x-ray diffraction pattern having characteristic peaks of 2θ at approximately 4.7, 9.4, 10.0, 11.0, 12.5, 14.2, 15.4, 16.1, 18.6, 19.0, 22.2, and 26.8 ° positions. . 33. The crystalline polymorph of claim 32, wherein the crystalline polymorph exhibits a powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern of FIG. 30. The method of any one of claims 19-29, wherein compound I is a crystalline polymorph according to any one of claims 32-35. The tablet form of the crystalline polymorph of claim 32. Crystalline polymorphic form of Compound I showing a powder x-ray diffraction pattern with characteristic peaks of 2θ at approximately 8.8, 9.2, 13.5, 19.1, and 24.4 ° positions. The crystalline polymorph of claim 38, wherein the crystalline polymorph exhibits a powder x-ray diffraction pattern having characteristic peaks of 2θ at approximately 6.7, 8.8, 9.2, 13.5, 15.0, 17.7, 19.1, 19.7, 21.4, and 24.4 ° positions. The powder of claim 38, having a characteristic peak of 2θ at approximately 6.7, 8.8, 9.2, 13.5, 14.1, 14.5, 15.0, 16.2, 17.0, 17.7, 19.1, 19.7, 21.4, 22.2, 24.1, 24.4, and 28.1 °. Crystalline polymorph showing an x-ray diffraction pattern. The crystalline polymorph of claim 38, wherein the crystalline polymorph exhibits a powder x-ray diffraction pattern substantially the same as the powder x-ray diffraction pattern of FIG. 2. 30. The method of any one of claims 19-29, wherein compound I is a crystalline polymorph according to any of claims 38-41. 39. The tablet form of the crystalline polymorph of claim 38. A composition comprising an amorphous form of compound I. Mesylate salt of compound I. Tosylate salt of compound I. Maleate salt of compound I. Oxalate salt of compound I. Dichloroacetate salt of compound I. Novel polymorphs, salts and compositions of Compound I, and methods for their preparation, substantially as described above.

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